MX2008006784A - Novel dual nk2/nk3-antagonists, pharmaceutical compositions comprising them and processes for their preparations - Google Patents

Abstract

The present invention relates to novel dual NK2/NK3-antagonists of formula (I) wherein the meaning of X and R1 to R5 is defined in the claims and in the description and also to pharmaceutical compositions comprising these compounds. Furthermore, the invention relates to processes for the preparation of the novel dual NK2/NK3-antagonists and to their uses.

Description

NEW ANTAGONISTS OF NK2 / NK3 DUALES. PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND AND PROCEDURES FOR YOUR PREPARATION Description The present invention relates to novel dual NK2 / NK3 antagonists and also to pharmaceutical compositions comprising these compounds. In addition, the invention relates to processes for the preparation of the new dual NK2 / NK3 antagonists. Neurokinins (NKs), also known as tachykinins, include the neuropeptides that occur in nature substance P, neurokinin A, and neurokinin B. Tachykinins act as receptor agonists that appear in higher mammals and humans, such as such as the neurokinin-1 receptor, the NK-2 receptor and the NK-3 receptor. Artificially prepared compounds, which are antagonists to tachykinin receptors, are usually classified according to their relative ability to bind to one or more of the three receptor subtypes mentioned above. In the physiological process tachykinins play, p. eg, an important role in the transmission of pain, emesis, neurogenic inflammation, inflammation of the bladder, inflammatory diseases of the joints or asthmatic ailments. Recently, a review article on NK receptor antagonists was published by Gerspacher (Progress Medical Chemistry, 2005, Vol. 43, 49 to 103), providing insights into recent developments in selective receptor antagonists (receptor antagonists). of NK1 or NK2 or NK3) and of combined receptors (NK1 / NK2; NK1 / NK2 / NK3; and NK2 / NK3).

The class of combined NK2 / NK3 receptor antagonists seems to be limited by two approaches of GSK and Sanofi. GSK preferred a stepwise modification of the structure of the selective antagonist of NK3 talnetant, by introducing a variety of substituents in the meta position of the quinoline moiety of the molecule. A very effective compound is the following: Sanofi-Syntheselabo describes in WO 2002/094821 (published November 28, 2002) a series of piperidine carboxamide derivatives of the following cyclic, non-linear general structure: Sanofi-Synthelabo reports a strong affinity of the NK2 receptor with a Ki value of 0.04 nM and a strong affinity of the NK3 receptor with a Ki value of 0.04 nM. However, to date no compounds with a linear core with a selective affinity of the NK3 receptor or an affinity of the combined NK2- / NK3 receptor have been reported. Therefore, an object of the present invention was to provide new active compounds with a linear nucleus with antagonist properties to tachykinin receptors NK2 and / or NK3. These compounds appear to be particularly suitable for the treatment of a variety of disorders. Surprisingly, it has now been found that a group of novel linear core compounds is distinguished by properties antagonistic to tachykinin receptors, in particular to NK2 and / or NK3 receptors. Accordingly, the group of compounds according to the invention appears to be particularly suitable for the treatment of peripheral disorders in which tachykinins, in particular neurokinin A and / or neurokinin B, participate as transfer agents, for example for the treatment and / or the prophylaxis of any pathology in which neurokinin A and / or NK2 receptors, or neurokinin B and / or NK3 receptors, or both neurokinin A and neurokinin B and / or NK2 and NK3 receptors are involved. In more detail, the compounds of the present invention appear to be particularly suitable for the treatment and / or prophylaxis of pathologies of the respiratory, gastrointestinal, urinary, immune and cardiovascular systems and of the central nervous system, as well as pain, migraine, inflammation , nausea and vomiting, and skin diseases. Even in greater detail, the compounds of the present invention appear to be particularly suitable for the treatment and / or prophylaxis of pathologies of respiratory diseases, in particular asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, bronchitis, cough and rhinitis.; skin diseases, in particular inflammatory reactions of the skin, allergic skin reactions and psoriasis; arthropathy diseases, in particular arthritis, vasculitis and systemic lupus erythematosus; functional disorders or inflammations in the gastrointestinal tract, in particular pseudomembranous colitis, gastritis, acute and chronic pancreatitis, ulcerative colitis, Crohn's disease and diarrhea; bladder diseases such as cystitis and interstitial cystitis; cardiovascular diseases such as hypertension, cancer treatment, especially melanomas, gliomas, small cell and large cell lung cancers, diseases of the immune system, bipolar disorders; migraine; pain, anxiety, depression, cognitive disorders, somatic disorders related to stress, psychosis, in particular schizophrenia, mania, schizoaffective disorder and panic disorders. The object of the present invention are compounds of general formula I, wherein: R1 is selected from the group consisting of: alkyl and cycloalkyl, R2 is selected from the group consisting of: alkyl, cycloalkyl, aryl, alkylenearyl, alkenylenaryl, heteroaryl and heterocyclic ring, R3 and R4 are independently selected from the group it consists of: hydrogen, halogen, hydroxyl, cyano and carboxyalkyl, X is selected from the group consisting of: CR6 and nitrogen, R5 is selected from the group consisting of alkyl optionally substituted with (CO) mNR9R10, cycloalkyl optionally substituted with (CO) mNR9R10, and NR7R8, R6 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and (C0) mNR9R10, R7 and R8 are independently selected from the group consisting of: alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, COalkyl, COAlkyl, or wherein R7 and R8 together form a 5-7 membered ring, which optionally contains an additional heteroatom, wherein said ring may be substituted with CONR9R10, and wherein in a 6-membered ring none of the ring atoms is replaced by carbonyl, R9 and R10 are independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, or wherein R9 and R10 together form a 5- to 7-membered ring, optionally containing an additional heteroatom, m is selected from 0 or 1, and acid addition salts, physiologically compatible , of formula I. Further, another object of the present invention are pharmaceutical compositions comprising the compounds of formula I. Yet another object of the present invention These are processes for the preparation of the compounds of formula I. In cases where in the compounds of formula I or in other compounds described within the scope of the present invention the substituents are or contain alkyl and / or alkylene, these may they are in each case straight or branched chain and have from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 7 carbon atoms, and even more preferably from 1 to 4 carbon atoms . The most preferred linear alkyl and / or alkylene group is methyl and / or methylene, respectively. The most preferred alkyl and / or branched alkylene group is Isopropyl and / or isopropylene, respectively. In the cases where in the compounds of formula I or in other compounds described within the scope of the present invention the substituents are or contain cycloalkyl and / or cycloalkylene, they may possess from 1 to 20 carbon atoms, preferably 1. to 10 carbon atoms, more preferably from 1 to 7 carbon atoms, and even more preferably from 1 to 4 carbon atoms. The most preferred cycloalkyl and / or cycloalkylene groups are cyclopentyl and cyclohexyl and / or cyclopentylene and cyclohexyllene, respectively. In the cases in which in the compounds of formula I or in other compounds described within the scope of the present invention, the substituents are or contain alkenyl and / or alkenylene, these can be in each case straight-chain or branched and have at 20 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 7 carbon atoms, and even more preferably from 2 to 4 carbon atoms. The most preferred alkenyl and / or alkenylene group is ethenyl and / or ethenylene, respectively. In case the substituents in compounds of formula I are or contain halogen, fluorine, chlorine or bromine are suitable. Chlorine is preferred. In cases where substituents on compounds of formula I are or contain carboxyalkyl, -OC (O) alkyl or C (O) O-alkyl, OC (O) alkyl is preferred. In cases where substituents on compounds of formula I are or contain aryl and / or arylene, monocyclic, bicyclic, tricyclic and tetracyclic aromatic ring systems are suitable. Phenyl is preferred. In cases where substituents on compounds of formula I are or contain heteroaryl and / or heteroarylene, systems of monocyclic, bicyclic, tricyclic and tetracyclic aromatic rings containing at least one heteroatom such as nitrogen. In cases where substituents on compounds of formula I are or contain heterocyclic rings, monocyclic, bicyclic, tricyclic and tetracyclic nonaromatic ring systems containing at least one, if not two or three or even four heteroatoms such as nitrogen are suitable. and / or sulfur and / or oxygen. A monocyclic ring system is preferred. Nitrogen and / or oxygen are preferred as heteroatoms. In the cases where R7 and R8 and / or R9 and R10 together form a ring of 5 to 7 members and where, in a particular embodiment, each of these rings, independently, optionally contains an additional heteroatom, said heteroatom can be selected from nitrogen, oxygen and sulfur, preferably oxygen. In the case that in the compounds of formula I or other compounds described within the scope of the present invention are or contain alkyl and / or alkylene, alkyl and / or alkylene, aryl and / or arylene, heteroaryl and / or heteroarylene, rings heterocyclic, all of these substituents may be further substituted with any of: alkyl, alkenyl, hydroxyl, SH, carbonylalkyl, carboxyalkyl, carbonylaryl, carboxyryl, carbonylheteroaryl, carboxyalkylearyl, carbonylheterocyclic ring, carboxyheterocyclic ring, halogen, cyano, oxyalkyl, oxyalkenyl, aryl, heteroaryl , N02, S02R11 and S03R11. In a preferred embodiment of the present invention, in compounds of formula I, R1 is methyl. In another preferred embodiment of the present invention, R3 and R4 are independently selected from the group consisting of: hydrogen, fluorine, chlorine, preferably hydrogen or chlorine. In a third preferred embodiment of the present invention, in compounds of formula IX is CR6, R5 is NR7R8 and R6 is (CO) mNR9R10, with m = 1. In another preferred embodiment of the present invention, in compounds X is N, R5 is cycloalkyl substituted with (CO) mNR9R10, and m = 1. In a fourth preferred embodiment of the present invention, in compounds of formula I, R7 and R8 together form a 6-membered ring, or R7 and R8 together form a ring of 6 members replaced with CONR9R10. In a fifth embodiment of the present invention, in compounds of formula I R9 and R10 are both methyl, or R9 and R10 together form a 6-membered ring, or R9 and R10 together form a 5-membered ring substituted with carbonyl. In another preferred embodiment of the present invention, in compounds of formula I R2 is selected from the group consisting of: Ci to C20 alkyl; C3 to C20 cycloalkyl; C2 to C2o alkenyl wherein each of R11 to R16 are independently selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, hydroxyl, alkoxy, cyano, N (H) C (O) O-alkyl, aminoalkyl, dialkylamino, OCF3, CF3 , carboxyalkyl, S (0) 2 NH2, phenyl, alkyl and cycloalkyl, wherein each of R18 and R19 are independently selected from the group consisting of: hydrogen, cyano and aryl, where t is 0 or 1, wherein each Q is independently selected from the group consisting of: CR11 and N, wherein Y is selected from the group consisting of: CH, N and NO, wherein Z is selected from the group consisting of: C-benzyl, NH, N -benzyl, N-alkyl, O and S, wherein each V is independently selected from the group consisting of: N and CR17, and wherein R17 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl, aryl and thioalkyl. In another preferred embodiment of the present invention, R5 is selected from the group consisting of: Particular embodiments of the present invention are the following compounds: Dimethylamide of 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] ] bipperidinyl-4'-carboxylic acid; 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4'-carboxylic acid methylamide; 1 '- [4- (cyclohexanecarbonyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] -bipiperidinyl-4'-carboxylic acid dimethylamide; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [(4-fluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] b-piperidinyl-4'-carboxylic acid; ester 4-. { [2- (3,4-dichloro-pheny] -4- (4'-dimethylcarbamoyl- [1,4 '] bipiperidinyl-1'-yl) -butyl] -methylcarbamoyl} -acetic acid acetic acid; 1'- acid dimethylamide. { 3- (3) 4-dichloro-phenyl) -4 - [(4-hydroxy-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 2- ester. { [2- (3,4-dichloro-phenyl) -4- (4'-d, methylcarbamoyl- [1,4'-bipiperidinyl-1'-yl] -butyl] -methyl-carbamoyl} -acetic acid acetic acid; 1 '- [4 - [(3-chloro-4-fluoro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] dimethylamide peridinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(3,5-difluoro-benzoyl) -methyl-amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid; 1 '- [4 - [(5-chloro-2-fluoro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] dimethylamide [1, 4'] β-piperidinyl-4'-carboxylic acid; dimethylamide of 1 '- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (naphthalene-1-carbonyl-3-cyano) -amino] -butyl} [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2-hydroxy-benzoyl) -methyl-amine] -buu? Hl-bipiperidine-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2,4-difluoro-benzoyl) -methyl-amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(3,4-d.fluoro-benzoyl) -methylamino-J-butyl-1H-pipperidine-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2,5-difluoro-benzoyl) -methyl-amine] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2,3,4-trifluorobenzoyl) -amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (1-oxy-pyridine-4-carbonyl) -amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(6-chloro-pyridine-3-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1, 4'] dimethylamide bipiperidin-4'-carboxylic acid; dimethylamide of 1 '- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-3-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethyl amide of 1 '- [4 - [(3-benzyl-2-methylsulfanyl-3H-imidazole-4-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (4-oxo-2-phenyl-4H-chromene-3-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethyl amide of 1 '- [4- (cyclopropanecarbonyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipperidinyl-4'-carboxylic acid; dimethylamide of 1 '- [4- (cyclopentanecarbonyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-methylamino-benzoyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; N- [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4 '] bipiperidinyl-1'-yl) -butyl] -N-methyl-phthalamic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(4-methoxy-benzoyl) -methyl-amino] - butl} - [1, 4 '] bipperidinyl-4'-carboxylic acid; dimethyl amide of 1 '- [4 - [(biphenyl-4-carbonymethyl-aminol-S-1S-dichloro-phenyl-butyl-II-1-piperidine-carboxylic acid dimethylamide] dichloro-phenyi-KS-S-diphenyl-propyoni-methyl-amino] -butyl.} - [1,4 '] -piperidinyl-4'-carboxylic acid dimethylamide 1' - (3- ( 3,4-dichloro-phenyl] -4- { [3- (4-hydroxy-phenyl) -propionyl] -met-1-amino} -butyl) - [1,4 '] bipiperidinyl 4'-carboxylic acid, 1 '-. {3- (3,4-dichloro-phenyl) -4- [methyl- (1-methyl-1H-pyrrolo-2-carbonyl) -amino] - dimethylamide butyl.) - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1' -. {3- (3,4-dichloro-phenyl) -4 - [(furan-2-carbonyl ) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1' -. {3- (3,4-dichloro-phenyl) -4- [methyl- (naphthalene-2-carbonyl) -amino] -butyl.] - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1' - [4 - [(2-biphenol-4 -yl-acetyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carbo xylic acid dimethylamide 1 '- [4-. { [3- (4-chloro-phenyl) -acyloyl] -methyl-amino} -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (1 H -pyrrolo-2-carbonyl) -amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(furan-2-carbonyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (thiophene-2-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidin-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (thiophene-3-carbonyl) -amino] -butyl} - [1, 4 '] bipyperidinyl-4'-carboxylic acid; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(1 H -indole-3-carbonyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2-1H-indol-3-yl-acetyl) -methyl-amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(1 H -indole-5-carbonyl) -methyl-aminol-butyl-11-jbipiperidinyl-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyrazine-2-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'- carboxylic; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-2-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-4-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethylamide of 1 '- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (4-oxo-4H-chromene-2-carbonyl) -amino] -butyl} - [1,4 '] -pipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (4-sulfamoyl-benzoyl) -methyl-amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(4-chloro-3-sulfamoyl-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl- dimethylamide 4'-carboxylic; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2-1H-imidazol-4-yl-acetyl) -methyl-amino-butyl-1H-pipperidine-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-2-yl-acetyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-3-yl-acetyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-4-yl-acetyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(1-acetyl-piperidine-4-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1, 4'] dimethylamide bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (tetrahydro-pyran-4-carbonyl) -amino] -butyl} - [I] jbipiperidinyl-carboxylic acid; (4 { [2- (3,4-Dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4 '] bipperidinyl-1'-yl) butyl tert-butyl ester butyl] -methylcarbamoyl] -phenyl) -carbamic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(3- [trifluoromethyl-methoxy] -benzoyl) -methyl-amino] -butyl ester} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethyllamide of 1 '- (3- (3,4-dichloro-phenyl) -4- { [2- (2,4-di { trifluoromethyl.} - phenyl] -acetyl] -methyl-amino} -butyl) - [1,4'-bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4-. { [2- (2,6-dihydroxy-pyrimidin-4-yl) -acetyl] -methyl-amino} -butyl) - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 4- tert.-butyl ester. { [2- (3,4-dichloro- phenyl) -4- (4'-dimethylcarbamoyl- [1, 4 '] bipiperidinyl-1'-yl) -butyl] -methylcarbamoyl} -piperidine-1-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(1 H-imidazole-4-carbonyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; (1- {[[2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4] bipiperidinyl-1'-yl) butyl tert-butyl ester butyl] -methyl-carbamoyl.} -2-phenyl-ethyl) -carbamic acid; [2- (3,4-Dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1, 4,] b-piperidinyl-1'-yl) -butyl] -methyl tert-butyl ester -carbamic; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(furazan-3-carbonyl) -methyl-amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2,2-difluoro-benzo [1,3] dioxol-5-carbonyl) -methyl-amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl-1H-pyrrolo-S-carbonyl-amino-butyl-1-phenylpiperidinyl] -carboxylic acid; 1 '- (3- (3,4-dichloro-phenyl) -4- { [3- (4-fluoro-phenyl) -5-methyl-isoxazole-4-carbonyl] -methyl-dimethylamide amino} -butyl) - [1,4 '] biphenylperidyl-4'-carboxylic acid; 1 '- (3- (3,4-dichloro-phenyl) -4- { [5- (4-methoxy-phenyl) -oxazole-4-carbonyl] -methyl-amino acid dimethylamide. -butyl) - [1, 4 '] bipperidinyl-4'-carboxylic acid; acid dimethylamide 1 '-. { 3- (3,4-dichloro-phenyl) -4- [methyl- (5-methyl-1-phenyl-1 H- [1,2,3] triazole-4-carbonyl) -amino] -butyl ester} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(benzofuran-5-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] dimethylamide bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (5-methyl-benzo [b] thiophene-2-carbonyl) -amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(3,5-bis-trifluoromethyl-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'-bipiper] dimethylamide dinium-4'-carboxylic acid; 1 '- [4 - [(2-bromo-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4'-carboxylic acid dimethylamide; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2-fluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethyllamide of 1 '- [3- (3,4-dichloro- phenyl) -4- (methvl-pentafluorobenzoyl-amino) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2,6-difluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(2,4-dichloro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipperidinyl- dimethylamide 4'-carboxylic; 1 '- [4 - [(2,6-dichloro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidine dimethylamide L-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-trifluoromethyl-benzoyl) -amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-methyl-benzoy-aminol-butyl-1-yl-1-bipiperidinyl) -carboxylic acid dimethylamide 1'-. {3- (3 , 4-dichloro-phenyl) -4 - [(3-fluoro-benzoyl) -methyl-amino] -butyl} - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1 - [4 - [(3-Chloro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl H1, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1' - [ 4 - [(3,4-dichloro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipperidinyl 4'-carboxylic acid 1'-. {3- (3,4-dichloro-phenyl) -4 - [(3-methoxy-benzoyl) -methyl-amino] -butyl} - acid dimethylamide. [1, 4 '] bipyperidinyl-4'-carboxylic acid dimethylamide 1'-. {3- (3,4-dichloro-phenyl) -4- [methyl- (3-trifluoromethyl-benzoyl) amino] -butyl} - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1' - [4 - [(4-chloro-benzoyl) -methyl-amino] -3- ( 3,4-dichloro-phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. {3- (3,4-dichloro-phenyl) -4 - [( 4-methoxy-benzoyl ) -methyl-amino] -butyl} - [1,4'-bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (4-trifluoromethyl-benzoi-aminol-butyl-1H-1-bipiperidine-carboxylic acid dimethylamide 1'-. {3- (3,4-dichloro phenyl) -4 - [(4-methyl-benzoyl) -methyl-amine] -butyl} - [1,4'-bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. {3- ( 3,4-dichloro-phenyl) -4 - [(2,2-dimethyl-propionyl) -methyl-amino] -butyl} - [1, 4 '] bipiperdinyl-4'-carboxylic acid dimethylamide; 1 '- [3- (3,4-dichloro-phenyl) -4- (methyl-phenylacetylamino) -butyl] - [1,4'] bipiperidinyl-4'- carboxylic; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-phenyl-cyclopropanecarbonyl) -amino] -butyl} - [1, 4 '] bipperidinyl-4'-carboxylic acid; 1 '- [4 - [(4-cyano-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4'-carboxylic acid dimethylamide; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (naphthalene-1-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethyllamide of 1'-4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl-butyl-1-pyridinylcarboxylic acid; dimethylamide of 1 'acid - [4- (benzoyl-methyl-amino) -3-phenyl-butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid ethyl-methyl-amide 1' - [4- (benzoyl- methyl-amino) -3- (3,4-dichloro-phenyl) -butyl- [1] bipiperidine-W-carboxylic acid; N-. {2- (3,4-dichloro-phenyl) -4- [4- (1 -dimethylcarbamoyl-cyclohexyl) -piperazin-1-yl] -butyl} -N-methyl-benzamide; dimethyl amide of 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro- phenyl) -butyl] - [1,4 '] bipperidinyl-2-carboxylic acid 1- [4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino] -3- dimethylamide (3,4-dichloro-phenyl) -butyl] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid dimethylamide 1- [4- (benzoyl-methyl-amino) -3- ( 3,4-dichloro-phenyl) -butyl] -4-pyrrolidin-1-yl-piperidin-4-carboxylic acid, N- [4- [4- (cyclopropylmethyl-propionyl-amino) -piperidin-1-) il] -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide; N ^ -IS ^ -dichloro phenyl ^ - ^ isopropyl-propionyl-amino-1-piperidin-1-yl] -butyl} -N-methyl-benzamide; N-. { 2- (3,4-dichloro-phenyl) -4- [4- (phenyl-propionyl-amino) -piperidin-1-yl] -butyl} -N-methyl-benzamide; N- [4- [4- (Butyl-propionyl-amino) -piperidin-1 -yl] -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide; N- [4 [4- (Butyl-cyclopropanecarbonyl-amino) -piperidin-1-yl] -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide; N- [4- [4- (Butyl-cyclohexanecarbonyl-amino) -piperidin-1-yl] -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide; N- [4- [4- (benzoyl-butyl-amino) -piperidin-1-yl] -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide; N- (2- (3,4-dichloro-phenyl) -4-. {4 - [(4-methoxy-butyl) -propionyl-amino] -piperidin-1-yl}. -butyl) -N- methyl-benzamide; N- [4-. { 4- [Cyclopropanecarbonyl- (4-methoxy- butyl) -amino] -piperidin-1-yl} -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide; N- [4-. { 4- [cyclohexanecarbonyl- (4-methoxy-butyl) -amino] -piperidin-1-yl} -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide; N- [4-. { 4- [benzoyl- (4-methoxy-butyl) -amino] -piperidin-1-yl} -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide; N- [4-. { 4- [cyclohexyl (propionyl) amino] 5 piperidin-1-yl} -2 - (3,4-dichlorophenyl) butyl] -N-methylbenzamide; N- [4-. { 4- [Cyclohexyl (cyclopropylcarbonyl) -amino] piperidn-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide; N- [4-. { 4- [Cyclohexyl (cyclohexylcarbonyl) amino] piperidin-1-yl} -2- (3,4-dichlorophenyl) -butyl] -N-methyl-benzamide; N- [4-. { 4- [benzoyl (cyclohexyl) amino] piperidin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide; N- [2- (3,4-dichlorophenyl) -4-. { 4 - [(1-or methylpiperidin-4-yl) - (propionl) amino] piperidin-1-yl} butyl] -N-methylbenzamide; N- [4-. { 4- [(Cyclopropyl-carbonyl) (1-methylpiperidin-4-yl) amino] piperidin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide; N- [4-. { 4 - [(cyclohexylcarbonyl) (1-methyl-piperidin-4-yl) amino] piperidin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide; N-. { 1 - [4- [Benzoyl (methyl) amino] -3- (3,4-dichlorophenyl) butyl] pyridin-4-yl} -N- (1-methylpiperidin-4-5 I) benzamide; N-. { 2- (3,4-dichloro-pheny!) -4- [4 '- (pyrrolidine-1-carbonyl) - [1,4'] bipperidinyl-1'-yl] -butyl} -N-methyl-benzamide; 1- [4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] -4- (2-oxo-) acid dimethylamide pyrrolidin-1-yl) -p -peridine-4-carboxylic acid; . { 2- (3,4-dichloro-phenyl) -4- [4 '- (piperidine-1-carbonyl) - [1,4'] bipiperidinyl-1'-yl] -butyl} 3-cyano-naphthalene-1-carboxylic acid methyl-amide; dipropylamide of 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] -piperidinyl-4'-carboxylic acid; 1- [4- (Benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] -4-morpholine-4-yl-piperidine-4-carboxylic acid dimethylamide; 1- [4- (Benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid isopropyl-methyl-amide; N-. { 2- (3,4-dichloro-phenyl) -4- [4- (piperidine-1-carbonyl) -4-pyrrolidin-1-yl-piperidin-1-yl] -butyl} -N-methyl-benzamide; dimethylamide of 1- [4- (benzoyl-methyl- amino) -3- (3,4-dichloro-phenyl) -butyl] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid; N-. { 2- (3,4-dichloro-phenyl) -4- [4- (morpholine-4-carbonyl) -4-pyrrolidin-1-yl-piperidin-1-yl] -butyl} -N-methyl-benzamide; and salts by the addition of physiologically compatible acids of these compounds. Particularly preferred are the following compounds: 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl-butyl-1-bipiperidine-carboxylic acid) methylamide 1' - [4-methylamide] - (benzoyl-methyl-amine) -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipperidinyl-4'-carboxylic acid dimethylamide 1' - [4- (cyclohexanecarbonyl methyl-amine) -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. {3- (3, 4-dichloro-phenyl) -4 - [(4-fluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic ester 4- { [2- (3,4-Dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4 '] bipiperidinyl-1'-yl) -butyl] -methyl-carbamoyl} -phenyl acid of acetic acid; dimethylamide of acid 1'-. {3- (3,4-dichloro-phenyl) -4 - [(4-hydroxy-benzoyl) -methyl-amino] -butyl} - - [1,4] bipiperidinyl-4 '-carboxylic ester 2- { [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4'] bipiperidinyl-1'-yl) -butyl] -methyl ester -carbamoyl.} -phenyl acid Ethical: 1 '- [4 - [(3-chloro-4-fluoro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1-dimethylamide] , 4 '] bipiperidinyl-4'-carboxylic acid; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(3,5-difluoro-benzoy-methyl-aminol-butyl-1-tl ^ -bipiperidinyl) -carboxylic acid dimethylamide 1 '- [4- [( 5-chloro-2-fluoro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'-bipiperidinyl-4'-carboxylic acid dimethylamide 1'- {3- (3,4-Dichloro-phenyl) -4- [methyl- (naphthalene-1-carbonyl-3-cyano) -amino] -butyl} - [1,4 '] -piperidinyl- 4'-carboxylic acid: 1 '-. {3- (3,4-dichloro-phenyl) -4 - [(2-hydroxy-benzoyl) -methyl-amino] -butyl H1,4'] b Picperidyl-4'-carboxylic acid dimethylamide 1'-. {3- (3,4-dichloro-phenyl) -4 - [(2,4-difluoro-benzoyl) -methyl-amino] -butyl .} - [1, 4 '] b-piperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(3,4-difluoro-benzoyl) -methyl-amino] -butyl-1, 4 '] bipperidinyl-4'-carboxyl co; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(2,5-difluoro-benzoyl) -methyl-amine] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2,3,4-trifluorobenzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(6-Chloro-pyridine-3-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [l]' jbipiperidinyl ^ '- dimethylamide carboxylic; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-3-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4- (cyclopentanecarbonyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidine-W-carboxylic acid dimethylamide; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-methylamino-benzoyl) -amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; N- [2- (3,4-Dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4 '] bipiperidinyl-1'-yl) -butyl] -N-methyl-phthalamic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(4-methoxy-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethyllamide of 1 '- (3- (3,4-dichloro-phenyl) -4- { [3- (4-hydroxy-phenyl) -propionyl] -methyl-amino} -butyl) - [1 , 4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (1-methyl-1 H -pyrrolo-2-carbonyl) -amino] -butyl ester} - [1, 4,] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(furan-2-carbonyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (naphthalene-2-carbonyl) -amino] -butyl} - [1 ^ 'jbipiperidiníW-carboxílico; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (1 H -pyrrolo-2-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [(furan-2-carbonyl) -methyl-amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethylamide of 1 '- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (thiophene-2-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [meth] - (thiophene-3-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(1 H -indole-5-carbonyl) -methyl-amino] -butyl H 1) 4,] b, piperidin-4 ' -carboxylic; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-2-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-4-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (4-oxo-4H-chromene-2-carbonyl) -amino] -butyl} - [I] jbipiperidiniW-carboxylic acid; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (4-sulfamoyl-benzoyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(4-chloro-3-sulfamoyl-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1, 4'] b, dimethylamide piperidinyl-4'-carboxylic acid; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-2-yl-acetyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-3-yl-acetyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-4-yl-acetyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (tetrahydro-pyran-4-carbonyl) -amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid; (4 { [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4 '] bipiperdinal-1' -butyl tert-butyl ester -yl) -butyl] -methyl-carbamoyl.} - phenyl) -carbamic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(3- [trifluoromethyl-methoxy] -benzoyl) -methyl-amino] -butyl ester} - [1, 4 '] b¡p¡per¡diln-4'-carboxylic; 1 '- (3- (3,4-dichloro-phenyl) -4- { [2- (2,4-di { trifluoromethyl.} - phenyl] -acetyl] -met-dimethylamide L-amino.} - butyl) - [1,4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2,2-difluoro-benzo [1,3] dioxol-5-carbonyl) -methyl-amino] -butyl} - [1, 4 '] b-piperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (5-methyl-1-phenyl-1 H- [1,2,3] triazole-4-carbonyl) -amino] - butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(benzofuran-5-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4'-carboxylic acid dimethylamide co; 1 '- [4 - [(2-bromo-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4'-carboxylic acid dimethylamide; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2-fluoro-benzoyl) -methyl-amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2,6-difluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(2,4-dichloro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] -piperidinyl- dimethylamide 4'- carboxylic; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-trifluoromethyl-benzoyl) -amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-methyl-benzoyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(3-fluoro-benzoyl) -methyl-amine] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(3-chloro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4'-carboxylic acid dimethylamide; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(3-methoxy-benzoyl) -methyl-amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (3-trifluoromethyl-benzoyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(4-methyl-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(4-cyano-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4 'dimethylamide -carboxylic; 1'4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino-S-1S-dichloro-phene-butyl-3, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamide co; 1 '- [4- (benzoyl-methyl-amino) -3-phenyl-butyl] - [1,4'] bipiperidinyl-4'-carboxylic acid dimethylamide; 1 '- [4- (Benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl- [1] -bipiperidinyl-carboxylic acid ethyl-methyl-amide; N-. { 2- (3,4-dichloro-phenyl) -4- [4- (1-dimethylcarbamoyl- cyclohexyl) -piperazin-1-yl] -butl} -N-methyl-benzamida; 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-2-carboxylic acid dimethylamide; 1- [4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] -4-pyrrolidin-1-dimethylamide -yl-piperidine-4-carboxylic acid; 5-1- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid dimethylamide; and salts by the addition of physiologically compatible acids of these compounds. More preferred compounds of the present invention are the following: 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-10 phenyl) -butyl] - [1,4'] dimethylamide bipperidinyl-4'-carboxylic acid; 1 '- [4- (cyclohexanecarbonyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4'-carboxylic acid dimethylamide; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(4-fluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; ester 4-. { [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl] [1,4'] bipiperidinyl-1'-yl) -butyl] -methylcarbamoyl} 5-acetic acid phenyl acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(4-hydroxy-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 2- ester. { [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4 '] bipperidinyl-1'-yl) -butyl] -methylcarbamoyl} -acetic acid acetic acid; dimethyl amide of 1 '- [4 - [(3-chloro-4-fluoro-benzoyl) -methyl-amino] -3- (S ^ -dichloro-phenyl-butyl-1-bipiperidinyl) -carboxylic acid dimethylamide; 1'- o. {3- (3,4-Dichloro-phenyl) -4 - [(3,5-difluoro-benzoyl) -methyl-amino] -butyl} - [1,4'-bipiperidinyl] - 4'-carboxylic acid 1'- [4 - [(5-chloro-2-fluoro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl-1-dimethylamide , 4 '] bipperidinyl-4'-carboxylic acid dimethylamide 1' -. {3- (3,4-dichloro-phenyl) -4- [methyl- (naphthalene-1 -carbonyl-3- cyano) -amino] -butyl} - [1,4'-bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. {3- (3,4-dichloro-phenyl) -4- 5 [( 2-hydroxy-benzoyl) -methyl-amino] -butyl} - - [1,4'] bipiperidinyl-4'-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2,4-difluoro-benzoyl) -methyl-amino-butyl-1H-pipperidine-M-carboxylic acid; dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [(3,4-difluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(2,5-difluoro-benzoyl) -methyl-amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid; 1 '- [4 - [(6-chloro-pyridine-3-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1, 4'] dimethylamide dipyridinyl-4'-carboxylic acid; 1 '- [4- (cyclopentanecarbonyl-methyl-amine) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] -piperidinyl-4'-carboxylic acid dimethylamide; 1 '- dimethylamide. { S-S ^ -dicloiO-phenyl ^ -Kfuran ^ -carboni-methyl-aminol-butyl-1-bipiperidine-W-carboxylic acid; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-2-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-2-yl-acetyl) -amino] -butyl ester} - [1, 4,] bipperidinyl-4, -carboxylic; 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-3-yl-acetyl) -amino] -butyl} - [1, 4 '] bipyperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(3- [trifluoromethyl-methoxy] -benzoyl) -methyl-amine] -butyl} - [I] 'Jiipiperidinyl-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (5-methyl-1-phenyl-1 H- [1,2,3] triazole-4-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid; 1 '- [4 - [(benzofuran-5-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperdinium-4 'dimethylamide -carboxylic; dimethyllamide of 1 '-4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipyperidinyl-4 '-carboxylic; 1- [4 - [(3-cyano-naphthalene-1-carbonyl) -methyl] -3- (3,4-dichloro-phenyl) -butyl] -4-pyrrolidin-1-yl dimethylamide -peridine-4-carboxylic acid; and salts by the addition of physiologically compatible acids of these compounds. The compounds of the formula I and their salts by addition of acids are they can be prepared by reacting a compound of the general formula II wherein R1 to R4 have the above meanings, with a compound of formula III wherein R5 has the above meaning, to result in a compound of the general formula I which, optionally, is converted to its salt by physiologically compatible acid addition. Alternatively, the compounds of the formula I and their acid addition salts can be prepared by reacting a compound of the general formula III wherein R5 has the above meaning, with a compound of general formula IV wherein R1, R3 and R4 have the above meanings, to give a compound of the general formula V, The compound of general formula V is then hydrolysed in an acidic medium to give a compound of general formula VI, wherein R1 and R3 to R5 have the above meanings. The compound of general formula VI is then reacted with a compound of formula VI i or R2? Cl v » where R2 has the above meaning, to result a compound of the general formula I which, optionally, is converted into its salt by physiologically compatible acid addition. Alternatively, the compounds of the formula I and their acid addition salts can be prepared by reacting a compound of the general formula X wherein Q is selected from the group consisting of: halogen, preferably bromine or iodine; and methylsulfonyl; with a compound of formula III to result in a compound of general formula I which, optionally, is converted to its salt by physiologically compatible acid addition. The compounds of formula II can be prepared by reacting a compound of formula VII or? Vil R2 Cl with a compound of formula VIII to give a compound of formula IX.

The compound of formula IX is then oxidized to a compound of formula II. The compounds of formula III are well known and can be prepared as described in any of J. Med. Chem. 1964, p. 619 (van de Westeringh); WO02 / 094821 (Sanofi); J. Org. Chem. 1980, 45, p. 3671 (J.T.Tai); J. Med. Chem. 1974, 9, p. 424 (B. Devaux); J. Med. Chem. 2002, 45, p. 3972 (J. T. Albert). A reaction scheme for the preparation of compounds of formula II is given in example 37. Compounds of formula IV can be prepared in a manner similar to that suggested for compounds of formula II, by selecting an appropriate R 2. The compounds of formula VII are known per se or can be prepared, in a known manner, by a person skilled in the art from known compounds. The compounds of formula X can be prepared by reacting a compound of general formula IX with Hhalogen, preferably HBr or Hl, to provide compounds of formula X wherein Q is a halogen, preferably bromine or iodine, or, alternatively, with methanesulfonyl chloride to provide compounds of formula X wherein Q is methylsulfonyl.

The compounds of formula I can be isolated from the reaction mixture and purified in a known manner. Acid addition salts can be converted to the free bases in a conventional manner, and these can be converted, if desired, in a known manner into physiologically compatible acid addition salts. The physiologically compatible salts of compounds of the general formula I are their conventional salts with inorganic acids, for example sulfuric acid, phosphoric acids or hydrohalic acids, preferably hydrochloric acid, or with organic acids, for example monocarboxylic, dicarboxylic or tricarboxylic acids, aliphatic, lower, such as maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, or with sulfonic acids, for example lower alkanesulfonic acids such as methanesulfonic acid or trifluoromethanesulfonic acid, or benzenesulfonic acids optionally substituted on the benzene ring with halogen or alkyl lower, such as p-toluenesulfonic acid. The compounds of formula I contain at the position and with respect to the nitrogen atom of the ring at the 4-position of the piperidine or piperazine ring, respectively, an asymmetric carbon atom, namely the carbon atom * C carrying the phenyl ring substituted with R3 and R4. Therefore, the compounds of formula I can be present in various stereoisomeric forms. The present invention covers both the mixtures of optical isomers and the isomerically pure compounds of formula I. Preference is given to compounds of formula I, in which the carbon atom * C carrying the phenyl ring substituted with R3 and R4 is present in the S-configuration. If mixtures of optical isomers of the starting compound are used, for example of the compounds of formula II or the compounds of formula IV, in the synthesis of the compounds of formula I, the compounds of formula I are also obtained in of mixtures of optical isomers. Starting from stereochemically uniform forms of the starting compound, stereochemically uniform compounds of formula I can also be obtained. Stereochemically uniform compounds of formula I can be obtained from mixtures of optical isomers in a known manner, for example by chromatographic separation on chiral separation materials or by reaction with suitable optically active acids, for example tartaric acid or l-oxanphosphonic acid, and subsequent separation into their optically active antipodes by fractional crystallization of the obtained diastereomeric salts. The compounds of formula I and their acid addition salts have properties that are antagonistic to tachykinin receptors and, therefore, are suitable for the treatment of disease states in higher mammals, particularly in humans, in which tachykinins they are involved as transfer agents. The group of compounds according to the invention is distinguished by an action profile particularly beneficial that is characterized by a high selectivity towards receptors of NK2 and / or NK3. In addition, the group of compounds according to the invention is distinguished by a good compatibility, even over prolonged periods of administration, and by a comparatively good oral availability. Due to their action profile, the compounds of formula I are suitable, in particular, for inhibiting processes in which tachykinins are involved, such as neurokinin A, which binds to NK2 receptors, and / or neurokinin B, which binds to NK3 receivers. Due to the action that is advantageously directed in the peripheral region, the compounds of formula I are suitable, in particular, for the treatment and / or prophylaxis of any pathology in which neurokinin A and / or NK2 receptors, or neurokinin B and / or NK3 receptors, or both neurokinin A are involved. and neurokinin B and / or NK2 and NK3 receptors. Some compounds of the present invention and, in particular, those wherein R 2 is a cyano-substituted naphthalene ring system, are also suitable for inhibiting processes in which tachykinins, such as substance P, are bound to receptors of NK1. Due to the action advantageously directed to the peripheral region, compounds of formula I, wherein R 2 is a cyano-substituted naphthalene ring system, are suitable, in particular, for the treatment and / or prophylaxis of any pathology in that are involved substance P and / or NK1 receptors, or neurokinin A and / or NK2 receptors, or neurokinin B and / or NK3 receptors, or any combination of two or all three substance P. neurokinin A and neurokinin B and / or NK1, NK2 and NK3 receptors. In more detail, the compounds of the present invention appear to be particularly suitable for the treatment and / or prophylaxis of pathologies of the respiratory, gastrointestinal, urinary, immune and cardiovascular systems and the central nervous system, as well as pain, migraine, inflammation, nausea and vomiting, and skin diseases. Even in greater detail, the compounds of the present invention appear to be particularly suitable for the treatment and / or prophylaxis of pathologies of respiratory diseases, in particular asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, bronchitis, cough and rhinitis; skin diseases, in particular inflammatory reactions of the skin, allergic skin reactions and psoriasis; arthropathy diseases, in particular arthritis, vasculitis and systemic lupus erythematosus; functional or inflammatory disorders in the gastrointestinal tract, in particular pseudomembranous colitis, gastritis, acute and chronic pancreatitis, ulcerative colitis, Crohn's disease and diarrhea; bladder diseases such as cystitis and interstitial cystitis; cardiovascular diseases such as hypertension, cancer treatment, especially melanomas, gliomas, small cell and large cell lung cancers, diseases of the immune system, bipolar disorders; migraine; pain, anxiety, depression, cognitive disorders, somatic disorders related to stress, psychosis, in particular schizophrenia, mania, schizoaffective disorder and panic disorders. Functional disorders in the gastrointestinal tract that can be treated by the compounds according to the invention include, in particular, disorders of the lower intestinal tracts known under the name of "irritable bowel syndrome" (= IBS) . Typical symptoms for the diagnosis of IBS are described, for example, in W.G. Thompson et al., Gastroenterology International 2 (1989) 92-95 or in W.G. Thompson et al., GUT 45/11 (1999) II43-II47, and are generally known among experts by the expression "Rome Criteria". The essential symptoms of IBS include, therefore, pain in the lower abdomen, which appears to be due to a hypersensitivity of the afferent visceral nervous system, and abnormalities in bowel movement, such as constipation, diarrhea or alternating constipation and diarrhea. Additional inflammatory disorders in the gastrointestinal tract that can be beneficially influenced by the group of compounds according to the invention are, for example, inflammatory disorders in the regions of the small and large intestine, usually covered by the expression " inflammatory bowel "(= IBD = for example ulcerative colitis or Crohn's disease). Due to their mechanism of action, the compounds according to the invention also appear to be suitable for the treatment of other disorders in which tachykinins and, in particular, neurokinin A, are involved as transfer agents. These disorders include, for example, neurogenic inflammation, inflammatory diseases of the joints, such as rheumatic arthritis, asthmatic complaints, allergic disorders, disorders of immune regulation, inflammation of the bladder or also functional dyspepsia. Another advantage of the compounds of the present invention is the synergistic effect between the profile of NK2 and NK3. Another advantage of the compounds of the present invention is their combined NK2 and NK3 profile, very well balanced. Description of the pharmacological test methods The example numbers given for the compounds of formula I, used as test substances in the given pharmacological tests. below, refer to the preparation examples described below. 1. Determination of the binding power of the test substances to NK1 receptors in vitro The affinity of the test compounds for NK1 receptors can be determined by measuring the ability of the test compound to displace a radiolabelled ligand from its binding site specific. The tests were conducted at Solvay Pharmaceuticals, Weesp, Holland. The radiolabel used in this assay is [3H] -substance P. The receptors were obtained from membrane preparations of CHO cells (Chimney Hamster Ovary cells = Chinese hamster ovaries), in which the NK1 receptor was stably expressed. human. The membranes were incubated with [3 H] -substance P in the absence or presence of test compounds at different concentrations, diluted in a buffer system. The separation of bound radioactivity from free radioactivity was effected by filtration through glass fiber filters (Packard GF / B) with several washes with ice-cold buffer solution. The bound radioactivity was measured with a liquid scintillation counter (total binding). Non-specific binding was determined by incubation with an excess (1 μmol / l) of unlabeled substance P. The specific union is obtained by subtracting the nonspecific binding of the total union. The radioactivity of the specific binding was plotted against the concentration of the test compound and the IC50 values were calculated, i.e. the concentration of test compound to which the radioligand is displaced by 50%. The inhibition constant (Ki) was calculated according to the Cheng-Prusoff equation, and is listed as its negative logarithmic value (pKi). The pKi value describes the power of a test compound to bind to a receptor.

Table 1: Potency of binding of test substances to NK1 receptors in vitro For the compounds of all the examples, the affinity to human NK1 receptors was determined in each case by at least three measurements of the test substances in series of concentrations of 10 ~ 6 to 10"10 mol / I. The average result of all measurements are listed above The compounds of Examples Nos. 1, 4, 8 to 11, 14, 15, 24, 49, 55, 56, 65, 70, 80, 82, 83, 89, 92, 93 , 98, 101 to 103, 105, 108, 116 and 125 to 127 exhibited pKi values of at least 7.0 in this test model. The compounds of Examples Nos. 11, 93, 98, 101, 102 and 126 exhibited pKi values of at least 8.0. 2. Determination of the binding power of the test substances to NK2 receptors in vitro The affinity of the test compounds for NK2 receptors can be determined by measuring the ability of the test compound to displace a radiolabelled ligand from its binding site specific. The radiolabel used in this assay is [3 H] -SR 48968 (saredutant). The receptors were obtained from membrane preparations of CHO cells (Chinese hamster ovarian cells), in which the human NK2 receptor was stably expressed. The membranes were incubated with [3H] -saredutant in the absence or presence of test compounds at different concentrations, diluted in a buffer system. The separation of bound radioactivity from free radioactivity was effected by filtration through glass fiber filters (Packard GF / B) with several washes with ice-cold buffer solution. The bound radioactivity was measured with a liquid scintillation counter (total binding). The non-specific binding was determined by incubation with an excess (0.1 μmol / l) of the specific binding is obtained by subtracting the nonspecific binding of the total union. The radioactivity of the specific binding was plotted against the concentration of the test compound and the CI5o values were calculated, ie the concentration of the test compound to which the radioligand is displaced by 50%. The inhibition constant (Ki) was calculated according to the Cheng-Prusoff equation, and is listed as its negative logarithmic value (pKi). The pKi value describes the power of a test compound to bind to a receptor.

Table 2: Potency of binding of test substances to NK2 receptors in vitro lEjempj .Nol, 37 38 39 40 41 42 43 44 45 pK; "$ ¿.. 8.8 8.8 7.7 7.9 8.5 7.8 9.6 8.3 8.6 For the compounds of Examples Nos. 1 to 47, 49 to 53, 55, 56, 58, 59, 61, 63 to 104 and 124 to 127, the affinity to human NK2 receptors was determined in each case by minus three measurements of the test substances in series of concentrations of 10 ~ 6 to 10 ~ 10 mol / l. The average result of all measurements is listed above. All of the aforementioned test substances exhibited pKi values of at least 7.0 in this test model. ! or The compounds of Examples Nos. 1 to 16, 18, 19, 23 to 26, 29 to 31, 35 to 38, 41, 43 to 47, 49, 55, 63, 67, 68, 71, 72, 74, 75, 77 to 80, 82, 83, 87, 91, 94 to 105, 108, 116, 124, 126 and 127 exhibited pKi values of at least 8.0. The compounds of Examples Nos. 1, 2, 4 to 6, 8, 9, 13 to 16, 95, 104 and 124 exhibited pKi values of at least 9.0. 3. Determination of the binding potency of the test substances a The affinity of the test compounds for NK3 receptors can be determined by measuring the ability of the test compound to displace a radiolabelled ligand from its specific binding site. 0 The radiolabel used in this test is [3H] -SR 142801 (osanetant). The receptors were obtained from membrane preparations of CHO cells (Chinese hamster ovarian cells), in which the human NK3 receptor was stably expressed. The membranes were incubated with [3 H] -osanetant in the absence or presence of test compounds at different concentrations, diluted in a buffer system. The separation of radioactivity bound free radioactivity was effected by filtration through glass fiber filters (Packard GF / B) with several washes with ice-cold buffer solution. The bound radioactivity was measured with a liquid scintillation counter (total binding). Non-specific binding was determined by incubation with an excess (1 μmol / l) of unlabeled osanetant. The specific binding is obtained by subtracting the non-specific binding of the total union. The radioactivity of the specific binding was plotted against the concentration of the test compound and the Cl 50 values were calculated, ie the concentration of test compound at which the radioligand is displaced by 50%. The inhibition constant (Ki) was calculated according to the Ceng-Prusoff equation, and is listed as its negative logarithmic value (pKi). The pKi value describes the power of a test compound to bind to a receptor. Table 3: Potency of binding of test substances to NK3 receptors in vitro Example No. l 97 98 99 101 102 103 104 124 125 pKÍ 7 1 7 2 7 2 7 7 7 0 7 0 7 7 7 8 7 3 For the compounds of Examples Nos. 1, 3 to 7, 9 to 16, 18, 19, 21 to 23, 25, 26, 29 to 33, 36 to 41, 43 to 47, 49 to 57, 60, 63 at 87, 89 to 91, 95, 97 to 104 and 124 to 126 the affinity to human NK3 receptors was determined in each case by at least three measurements of the test substances in series of concentrations of 10"6 to 10 ~ 10 mol / l The average result of all measurements is listed above. All of the aforementioned test substances exhibited pKi values of at least 7 0 in this test model. The compounds of Examples Nos. 1, 3 to 10, 14, 15 , 18, 23, 36, 43, 49 to 51, 53 to 56, 67, 68 and 83 exhibited pKi values of at least 8.0 4. FUNCTIONAL CELLULAR TESTS OF NK1 ANTAGONISM. NK2 and NK3 Cellular functional tests of the antagonist effect of the compounds of the present invention on human tachykinin receptors were performed on CHO cells expressing recombinant NK1, NK2 or NK3 human receptor. In these assays inhibition of ligand-induced increase in intracellular calcium mobilization and inhibition of mitogen-activated protein kinase (MAPK) ligand-induced phosphorylation were determined, which can be used as a measure of Functional activity of tachykinin antagonists. Additionally, the antagonistic properties of reference compounds on the different tachykinin receptors were characterized for comparative purposes. The effects of test compounds were fixed using cells from Chinese hamster ovarian fibroblasts (CHO), stably expressing cloned human NK1, NK2 or NK3 receptors. The NK receiver is coupled to Gq. Activation of the Gq protein by ligand binding to the receptor leads to intracellular calcium mobilization and MAPK phosphorylation. The two systems were used to determine functional effects of the test compounds. MEASUREMENTS OF CA2 + USING FLIPR FOR THE ACTIVITY OF NK1 AND NK2 For the tests, the cells were seeded, 24 hours before the experiment, in 96-well black microplates. The cell density was 2.2 x 10 4 cells / well. All stages were carried out in sterile conditions. In order to observe changes in intracellular calcium levels, the cells are loaded with a calcium-sensitive dye. This dye (FLUO-4, from Molecular Probes) excites at 488 nm, and emits in the range of 500 nm to 560 nm, only if a complex is formed with calcium. For the dye loading the growth medium was aspirated out of the well without disturbing the confluent cell layer and 100 μl of loading medium (HBSS, 4 μM FLUO-4, 0.005% pluronic acid (p / p) was dispensed into each well. v), 2.5 mM probenecid, 20 mM HEPES, pH 7.4) using an automatic pipetting system (Multídrop, Labsystems). Pluronic acid was added to increase the solubility of the dye and the uptake of dye into the cells, while probenecid, an anion exchange inhibitor, was added to the loading medium to increase retention of dye in the cells. The cells were incubated in an incubator with 5% C02 at 37 ° C for 40 minutes. After loading the dye, the cells were washed three times with wash buffer (HBSS, 2.5 mM probenecid, 20 mM HEPES, pH 7.4) to reduce basal fluorescence. In the last washing step, the buffer was aspirated and replaced by 100 μl of washing buffer. For the antagonist screening mode 50 μl of the compound (final concentration ranges from 10 μM to 1.4 nM) were applied 7 min before the addition of substance P (final concentration 10"8 M; NK1 agonist) or NKA (final concentration: 10"7 M, NK2 agonist) .The FLIPR adjustment parameters were established at an exposure duration of 0.4 s, filter 1, addition of 50 μl of fluid, height of the pipettor at 125 μl, dispensing speed 40 μl / s without mixing, maximum fluorescence changes were obtained using the statistical function of the FLIPR software, and data were plotted using GraphPad Prism 4. All points were expressed as percent inhibition of the control agonist The Cl50 values were determined using the sigmoidal adjustment of the dose-response curve. The values of the antagonist potencies (pA2) were calculated using the equation: pA2 = -log (Cl50 / (1 + [L] / EC50)), in which the Cl50 of the test compound was obtained from the concentration-effect relationships , [L] is the agonist concentration (substance P for the NK-i assay, NKA for the NK2 assay, NKb for the NK3 assay), and the EC50 is the agonist potency at the human NK receptor cloned respective (EC50 of substance P: 10"96 M; EC50 of NKA: 10" 8'8 M, EC50 of NKB: 10"8.8 M) The results are summarized in tables 4 and 5: Table 5: Data of pA2 for NK2: MEASUREMENTS OF CA2 + USING ECUORINE FOR NK3 ACTIVITY Antagonism of NK3 was measured in a cell line expressing the human NK3 receptor and mitochondrially directed apoequorin. In this system, cells expressing apoecuopne are incubated with coelenterazine, which is the ecuorin chromophore co-factor. After incubation of the cells with senktide, a potent agonist in NK3, the intracellular calcium concentration increases. Traces of free calcium lead to a concentration-dependent activation of the catalytic activity of ecuorin, which oxidizes coelenterazine and provides apoecuorine, coelenteramide, C02 and light (? Max = 469 nm). Once the photon has been emitted, the complex must dissociate and the apoequorin must recombine with the co-factor before the complex can emit another photon. Thus, in this system, luminescence measurements (light emission) after the addition of senktide reflect an increase in intracellular calcium due to the activation of NK3 receptors. For the test, the cells were grown to confluence and harvested with complexon (5 mM EDTA in PBS). Cells were centrifuged and resuspended in DMEM / F-12 (nutrient mixture according to Ham) without phenol red, supplemented with 10% FCS to a density of 5 x 10 6 cells / ml. In order to load the cells, coelenterazine was added to a final concentration of 5 μM and the cells were stirred at room temperature for 4 hours. The loaded cells were diluted in DMEM / F12 without phenol red or supplements to a density of 2.8 x 10 5 cells / ml, pre-heated to 37 ° C and shaken for 60 min at room temperature. For the antagonist screening mode, 15 μl of the cell suspension was added to 85 μl of the compound (final concentration ranges of 4.5 nM to 10 μM) in 96-well white plates. After an incubation time of 20 min 50 μl of senktide (final concentration of 5 x 10 ~ 8 M) was applied and the chemiluminescence was measured immediately for 20 seconds using the Microlumat (Berthold). All points were expressed as a percentage of inhibition of the control agonist. The IC50 values were determined using the sigmoidal fit of the dose-response curve of GraphPad Prism 4. The values of the antagonist potencies (pA2) were calculated using the equation: pA2 = pCI50 + log [(L / CE50) -1] , wherein pCI50 is the negative logaithm of the IC50 value of the test compound that was obtained from the concentration-effect relationships, L is the concentration of senktide and EC50 is the power at the cloned human NK3 receptor (EC50 of senktide: 10"8 8 M) Table 6: pA2 data for NK3: . Determination of functional NK1 receptor antagonism of test compounds in tissue isolated from guinea pigs. The antagonist action of NK1 of test compounds was tested in aortic ring preparations isolated from guinea pigs. The preparations were kept in an oxygenated nutrient solution, maintained at 37 ° C. To measure the contraction of the circular vascular muscle, the preparations were fixed to a hook and connected to force displacement transducers. Contractions / relaxations were recorded in a pen recorder. The preparations were given a medium shade by the addition of phenylephrine. The NK1 receptors were stimulated with the NK1 receptor agonist substance P, causing a relaxation of muscle tone. Before (predrug) and after the administration of the test compound said relaxations were measured and quantified as a percentage of relaxation by the predrug. 2-3 concentrations of the test compound were used, demonstrating the inhibition of the concentration of receptor stimulation in a dependent manner. The concentration of the semi-maximal inhibition (Cl50) and its negative logarithm pCI50 = -log (IC50) were calculated. The pIC50 value indicates the inhibitory potency of the test compounds with respect to the NK1 receptor.

Table 7: Functional antagonism of NK1 of test substances in guinea pig isolated tissue 6. Determination of functional NK2 receptor antagonism of test compounds in guinea pig isolated tissue. The antagonist action of NK2 of test compounds was tested in gallbladder preparations isolated from guinea pigs. The preparations were kept in an oxygenated nutrient solution, maintained at 37 ° C. To measure contraction of the gallbladder muscle, the preparations were fixed to a hook and connected to force displacement transducers. The contractions were recorded in a pen recorder. Receptors of NK2 were stimulated with the NK2 receptor agonist neurokinin A, causing a contraction of the muscle. Before (predrug) and after the administration of the test compound said contractions were measured and quantified as a percentage of the contraction by the predrug. 2-3 concentrations of the test compound were used, demonstrating the inhibition of the concentration of receptor stimulation in a dependent manner. The concentration of the semi-maximal inhibition (IC50) and its negative logarithm pCI50 = -log (Cl50) were calculated. The pCI50 value indicates the inhibitory potency of the test compounds with respect to the NK2 receptor. Table 8: NK2 receptor antagonistic efficacy of the test substances of formula I in the gallbladder of guinea pigs in vitro 7. Determination of functional NK3 receptor antagonism of 5 test compounds in tissue isolated from guinea pigs. The antagonist action of NK3 of test compounds was tested in isolated preparations of guinea pigs. The preparations were kept in an oxygenated nutrient solution, maintained at 37 ° C. To measure the contraction of the longitudinal muscle of the ileum, the preparations were fixed to a hook and connected to transducers of force displacement. The contractions were recorded in a pen recorder. Receptors of NK3 were stimulated with the NK3 receptor agonist [MePhe7] -neuroquinine B, causing a contraction of the muscle. Before (predrug) and after the administration of the test compound, c said contractions were measured and quantified as a percentage of the contraction by the predrug. 2-3 concentrations of the test compound were used, demonstrating the inhibition of the concentration of receptor stimulation in a dependent manner. The concentration of the semi-maximal inhibition (CI5o) and its negative logarithm pCI5o = -log (IC50) were calculated. The pCI5o value indicates the inhibitory potency of the test compounds with respect to the NK3 receptor. Table 9: Functional antagonism of NK3 of test substances in guinea pig isolated tissue 8. Determination of the NK3 receptor antagonist efficacy of test substances in vivo (reduction of body temperature in gerbils with senktide-induced hypothermia) NK3 agonists reduce the body temperature of gerbils. Senktide-induced hypothermia can be antagonized by administering compounds with NK3 antagonist properties. The measurement of the hypothermia level is indicative of the degree of activity of the test compounds. The proper effect of the tested compound is confirmed in the same experiment to exclude an additional hypothermia effect. Gerbil males with a body weight between 60 and 90 g are housed in groups at a normal day-night rhythm and under a constant temperature of the environment (ambient temperature: 21 ± 2 ° C) with a relative humidity level (50 ± 10 %).

Water and food are freely available. Reference agonist: senktida 0.03 mg / kg sc. Antagonists: see the compounds of the examples in Table X. By series of experiments, a condition is always the group of is always the vehicle / senktída group to determine the hypothermia induced by sinktide (= 100%). The animals are weighed and marked 60 minutes before the administration of the agonist. For oral (po) assays, the test compounds are administered at t = -60 minutes. For parenteral or subcutaneous administration (ip or sc, resp.), At t = -30 minutes. At t = 0 minutes, the senktide agonist (sc) is administered. At t = 15 minutes the temperature is measured orally, and recorded with an accuracy of 0.1 ° C after a reading of 10 seconds. From this way, animals are measured every 60 s. Using the Dunett test, the vehicle / vehicle group is used as a reference for the analysis of the own effect; while the vehicle / senktide group is used for comparative purposes for the interaction test (ie groups of compounds of the example / senktida). Table 10: Inhibition of temperature increase at t = 60 minutes after oral administration (po) Table 11: Inhibition of the increase in temperature at a dose of 10 mg / kg after parenteral administration (ip) 9. Determination of the NK3 receptor antagonist efficacy of test substances in vivo (reduction of blood pressure in guinea pigs with senktide-induced hypertension) NK3 agonists increase blood pressure in guinea pigs. The hypertension induced by senktide can be antagonized by administering compounds with NK3 antagonist properties. The measurement of the level of hypertension is indicative of the degree of activity of the test compounds. The proper effect of the tested compound is confirmed in the same experiment for exclude an effect of additional hypertension. Dunkin Hartley male guinea pigs with a body weight between 450 and 550 g were anesthetized with ketamine (200 mg / kg i.m., Aescoket 10%) and the left carotid artery and the left jugular vein were cannulated for blood pressure measurement and drug application, respectively. The animals were allowed to breathe spontaneously. Blood pressure was measured with a strain gauge transducer connected to a computer through an amplifier. After haemodynamic stabilization, two subsequent injections of the NK3 receptor agonist senktide (0.4 μg / kg iv, 0.5 ml / kg) were administered at a 15-minute interval and the peak pressure increase was determined, blood pressure served as the hypertensive effect of the predrug of senktide. Five minutes later, the compound was administered in the form of an infusion over 10 min (0.1 ml / min), followed immediately by an injection of 0.4 μg / kg of senktide and the peak increase in blood pressure was determined. median. Up to 5 cycles of additive test compound dosages were applied and after each dose the hypertensive effect of senktide was determined. The effect of the test compound on the peak increase in blood pressure induced by senktide is expressed as a percentage with respect to the value of the pre-drug. Values were calculated Dl50 (dose that produces a 50% inhibition of the senktide response) from the dose-response curve. The effect of the vehicle on the response of the pressure induced by senktide was determined on a regular basis. For oral administration, vehicle (1% methylcellulose) or test compound was administered in a dose volume of 5 ml / kg.

Forty-five minutes later, an anesthetic was induced and the carotid artery and jugular vein cannulated. After a 10-minute period for hemodynamic stabilization, two subsequent injections of the NK3 receptor agonist senktide (0.4 μg / kg iv, 0.5 ml / kg) were administered at a 15-minute interval and the peak pressure increase was determined. arterial blood pressure of each injection. The first injection of senktide was performed approximately 80 to 90 minutes after dosing. The median value of the increase in blood pressure served as the hypertensive effect of senktide in that animal. The median hypertensive effect of senktide after vehicle treatment served as the control value (100%). The effect of each dose of test compound on the peak increase in blood pressure induced by senktide is expressed as a percentage with respect to this control value and averaged for each dose group. DI50 values (dose that produces a 50% inhibition of the senktide response) were calculated from the dose-response curve. Senktida (0.8 μg / ml) was dissolved in saline. For intravenous administration, the test compounds were dissolved in 40% hydroxypropyl-β-cyclodextrin (HPCD) containing 10% DMSO, diluted with saline and administered intravenously at cumulative dose intervals. A vehicle vehicle group received the corresponding HPCD / DMSO solutions in place of the test compound. For oral administration, the test compound was suspended in 1% methylcellulose. A vehicle vehicle group received the corresponding HPCD / DMSO solutions in place of the test compound. Table 12: Inhibition of blood pressure as a Dl50 value after intravenous (iv) and oral (po) administration . Determination of the antagonist efficacy of the NK1 and NK2 receptors of the test substances in vivo The antagonist activities of NK1 and NK2 of the test substances were investigated in anesthetized guinea pigs, in each case after intravenous (= iv) and oral administration ( = po) in vivo. With the present test model it is possible to detect both antagonistic effects of NK2 in three different organ systems (respiratory tract, colon and circulation) and antagonistic effects of NK1 (rapid drop in blood pressure) in an animal simultaneously. Pirbright-White guinea pigs with a body weight of 500-700 g were anesthetized with ketamine / xylazine (67/13 mg / kg subcutaneously, initial dose, additional doses administered as required). The animals were provided with an intravenous catheter in order to administer the substance and a intra-artery catheter to measure blood pressure. The animals were ventilated artificially through a tracheal cannula, and the respiratory pressure was recorded by a pressure transducer. A balloon was introduced into the distal colon of the animals for the manometric recording of the mobility of the colon by means of a pressure transducer. Blood pressure, heart rate, respiratory pressure and colonic pressure were continuously measured for each animal and plotted on a recorder and by means of a digital data processing system. Neurokinin A (= NKA; 200 pmol / animal) was administered i.v. in the form of a bolus as a test stimulus to stimulate the NK1 and NK2 receptors. The injection of NKA resulted in an increase in the respiratory pressure (bronchoconstriction) and pressure of the colon, and a biphasic drop in blood pressure. The first phase of hypotension (= phase of maximum hypotension in the space of the first minute after the administration of NKA) is mediated through the NK-1 receptors, since they can be completely blocked by specific NK- receptor antagonists. 1. The second phase of delayed hypotension (= maximum hypotensive phase after 2-5 min), on the other hand, is mediated through NK-2 receptors, since they can be blocked by specific NK-2 receptor antagonists. The doses of the test substances are given as ED50 values, each of which results in a response to the stimulus of the NKA test that is reduced by 50% of the initial value, as characteristic variables of the individual bronchoconstriction measurement parameters, colonic pressure and change in blood pressure mediated by NK1 or NK2. The antagonistic effects of the test substances were first investigated in a cumulative manner, the time of the stimulation being NKA test for 1 min after completion of the administration of the respective doses of the test substances. These DE5o values obtained from the cumulative dose-effect curves are shown in Table 13. Table 13: Antagonistic potency of the NK1 and NK2 receptors of the test substances of formula I in guinea pigs in vivo after intravenous administration The measured values, shown in Table 14 shown above, show, among others, that the compounds of Example No. 11 after i.v. cumulative (detection of antagonism 1 min after having completed the administration of test substance) caused marked NK-1 receptor antagonist activity in early hypotension. The data further demonstrate that the compounds of all Example Nos. Caused marked NK2 receptor antagonistic activity of colonic mobility, late drop in blood pressure and respiratory resistance. In order to additionally detect the variation over time of the antagonistic effects of the test substances, the stimulus action of the NKA test was determined at different times (1, 30, 60, 90, 120, 150 and 180 min) after oral administration of the test substances. The antagonistic effects of the test substances were then determined as "area under the curve" ("AUC") throughout the investigation period after administration of the test substances (1- 180 min after administration) and the values DE50 after oral administration obtained therefrom are shown in Table 14. Table 14: Antagonistic potency of the NK1 and NK2 receptors of the test substances of formula I in guinea pigs in vivo after oral administration The compounds according to the invention, in particular the compounds of Examples Nos. 1, 4, 8 and 11 as shown in Table 15, are, in addition, orally active on NK2. Example 11 was also active as antagonists of the NK1 receptor. The compounds of formula I can be administered in conventional pharmaceutical preparations. The doses to be used can vary individually and, of course, will vary according to the type of condition to be treated and the substance used. In general, however, medicinal forms with an active substance content of 0.2 to 200 mg, in particular 1 to 50 mg, of active substance per individual dose are suitable for administration to humans and higher mammals. The compounds may be contained according to the invention, together with conventional auxiliary substances and / or pharmaceutical carriers, in solid or liquid pharmaceutical preparations. Examples of solid preparations are preparations that can be administered orally, such as tablets, coated tablets, capsules, powders or granules or, alternatively, suppositories. These preparations may contain conventional inorganic and / or organic pharmaceutical supports such as talc, lactose or starch, in addition to conventional pharmaceutical auxiliaries, for example lubricants or tablet disintegrating agents. Liquid preparations such as suspensions or emulsions of the active substances may contain the usual diluents such as water, oils and / or suspending agents such as polyethylene glycols and the like. Other auxiliary substances such as preservatives, flavor correctors and the like can be added additionally.

The active substances can be mixed and formulated, in a conventional manner, for example, with the auxiliaries and / or supports and can be granulated wet or dry. The granules or the powder can be poured directly into capsules or can be pressed to form tablet cores in a conventional manner. If desired, these can be coated in a known manner. It is intended that the following examples further explain the invention, without limiting its scope. The LC-MS (API) data were obtained by the following conditions: Description of the Instruments: API 100 Single Quad, PE Applied Biosystems PE 200 Bl LC Pump, PE Applied Biosystems Gilson XL 215 Autosampler, Gilson Inc. Broadcast Detector light Sedex 75, SEDERE Column: XTerra MS C18, 2.5 um, 50 x 4.6 mm Guard column: XTerra MS C18, 3.5 um, 20 x 3.9 mm Solvent A: NH4 ac 0.01 M pH 5.0 + 5% acetonitrile Solvent B: Acetonitrile Gradient profile: 100% A-10min - > 95% B 2 min Socratic 95% B 100% A - 0.5 min - 95% B 100% A 2.5 min Socratic Flow: 1.0 mi / min Wavelength: 225 nm LC-MS data (ZQ) were obtained by the following conditions: Instrument description: ZQ Single Quad, Waters / Micromass Alliance HT 2795, Waters Light Diffusion Detector PL-ELS 1000, Polymer Labs Column: XTerra MS C18, 2.5 um, 50 x 4.6 mm Guard Column: XTerra MS C18, 3.5 um, 10 x 2.1 mm Solvent A: NH4ac 0.01 M pH 5.0 + 5% acetonitrile Solvent B: Acetonitrile Gradient profile: 100% A 1 min Socratic 100% A - 6min - > 95% B 1 min Socratic 95% B 100% A - 1 min - 95% B 100% A 2 min Socratic Flow: 1.0 mi / min Wavelength: 205-350 nm Example 1: synthesis of? / - I (2S) -2- (3,4-dichlorophenyl) -4-oxobutyl] -? / - methyl-benzamide as a starting material for the preparation of the compounds of Example 1, 2 and 99 In a solution of 15 ml (0.172 mol) of oxalyl chloride in 200 ml of methylene chloride. Cooled to -60 / -70 ° C under nitrogen, they were added dropwise in 75 minutes in order to maintain the temperature at -60 / -70X 30 ml of DMSO in 100 ml of methylene chloride. The reaction mixture was stirred for 20 minutes at -70 ° C and, subsequently, a suspension of 31 g (0.088 mol) of N- [2- (3,4-dichloro-phenyl) -4-hydroxy-butyl] -N-methyl-benzamide in 200 ml of methylene chloride was added the space of 60 minutes in such a way that the temperature of the reaction mixture is maintained at -60 ° C. At this temperature, 90 ml of triethylamine in 40 ml of methylene chloride were added dropwise. The mixture was allowed to slowly return to room temperature and was allowed to stand for 15 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in a mixture of 200 ml of toluene and 200 ml of ethyl acetate. The organic phase was washed with 100 ml of a saturated solution of NaCl in water and 4 times with 100 ml of water each time. The recovered organic phase was dried over sodium sulfate and concentrated in vacuo to provide 32.6 g of a glassy material. 17.15 g of the compound were suspended in 10 ml of methylene chloride under stirring at room temperature. To the suspension 50 ml of n-hexane was added and the mixture was placed at 45 ° C giving a suspension. To the suspension was added 40 ml of n-hexane and the mixture was allowed to cool to room temperature. The suspension obtained was separated by filtration to give a solid which was washed three times with 10 ml of n-hexane. After dissolution in methylene chloride and subsequent concentration to dryness, 15 g of a solid were obtained (melting point: 78-79 ° C): overall yield: 90% Example 2: synthesis of 1 '- [(3S) -4-fbenzoyl (methyl) amino] -3- (3,4-dichlorophenyl) -butyl-1 -? /,? / - dimethyl-1,4'-bipiperidine-4'-carboxamide (compound of example 1) To a suspension of 15 g (0.0428 mol) of the aldehyde of example 1, 14. 9 g (0.0540 mol) of dimethyl amide hydrochloride of [1, 4 '] dipyridinyl-4'-carboxylic acid and 5.3 g of sodium acetate in 800 ml of THF at room temperature and under stirring were added 5 ml of acetic acid. and the mixture was stirred for 5 hours at room temperature. To the mixture was added portionwise 18.5 g (0.0876 mol) of sodium triacetoxy borohydride, and the mixture was further stirred at room temperature for 15 hours. The mixture was concentrated to dryness in vacuo and re-dissolved in 300 ml of ethyl acetate, 50 ml of MTBE and 6 g of KOH dissolved in 100 ml of water. The organic phase was washed with sodium hydrogen carbonate until pH 5-6 and 3 times with 100 ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness to give 27 g of the crude base as a foam. 17 g of crude base were dissolved in 30 ml of methylene chloride at room temperature to which 13 ml of 5N HCl in isopropanol were added and a solution was obtained. To the solution, 500 ml of MTBE was added and a solid appeared. The suspension was heated to 50 ° C and cooled. The solid was recovered by filtration, and washed 3 times with 100 ml of MTBE. The solid was dissolved in 100 ml of methanol and concentrated to dryness to give 16.2 g of the compound identified as dihydrochloride in elemental analyzes. Yield: 90% Optical rotation: -16.3 ° (c = 1% in methanol).

The crude base, purified by dissolving in water in the presence of concentrated HCl gives, after the elimination of insoluble by-products by extraction with MTBE and basification by means of KOH of the aqueous phase and subsequent extraction of the base using methylene chloride, a Pure base in the form of a yellowish compound with a 90% yield. Optical rotation; -17.8 ° (c = 1% in methanol). 1 H = NMR (as base) (500 MHz, CDCl 3, 30 ° C) d: 7.40-7.25 (m, 4.6H), 7.25-7.0 (m, 2.7H), 6.9, 6.7 (2 xs wide , 0.7H), 3.82 (broad s, 0.7H), 3.55 (dd, 0.7H), 3.5-3.25 (m, 4.4 H), 3.2 (broad s, 0.7H), 3.0 (m, 2H), 2.95- 2.90 (2xs, 3H), 2.8-2.5 (m, 4.5H), 2.4-1.6 (m, 12H), 1.5 (s, 4H), 1.4 (s, 2H). 13 C-NMR (125 MHz, CDCl 3, 30 ° C) d: 173.5, 171.6, 143.0, 136.4, 132.4, 130.5, 128.4, 126.8, 66.9, 57.1, 56.1, 53.3, 51.7, 47.3, 41.7, 38.7, 37.7, 33.6, 30.9, 26.9, 25.2. LC-MS: M + 1 (monoisotope) 573. Retention time: 7.90 min (API); 5.38 min (ZQ). Example 3: synthesis of 1 '- [(3S) -4-fbenzoyl (methyl) amino1-3- (3,4-dichlorophenyl) -butyl] -? / - methyl-1,4'-bipiperidine-4' -carboxamide (composed of example 2) To a suspension of 15 g (0.0428 mol) of the aldehyde of example 1, 14.1 g (0.0540 mol) of [1,4'-bipiperidinyl-4'-] methylamide hydrochloride. carboxylic acid and 5.3 g of sodium acetate in 800 ml of THF at room temperature under stirring were added 5 ml of acetic acid and the mixture was stirred for 5 hours at room temperature. To the mixture were added portionwise 18.5 g (0.0876 mol) of sodium triacetoxy borohydride, and the mixture was further stirred at room temperature for 15 hours. The mixture was concentrated to dryness in vacuo and re-dissolved in 300 ml of ethyl acetate, 50 ml of MTBE and 6 g of KOH dissolved in 100 ml of water. The organic phase was washed with sodium hydrogen carbonate until pH 5-6 and 3 times with 100 ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness to give 27 g of the crude base as a foam. 17 g of crude base were dissolved in 30 ml of methylene chloride at room temperature to which 13 ml of 5 N HCl in isopropanol were added and a solution was obtained. To the solution, 500 ml of MTBE was added and a solid appeared. The suspension was heated to 50 ° C and cooled. The solid was recovered by filtration and washed 3 times with 100 ml of MTBE. The solid was dissolved in 100 ml of methanol and concentrated to dryness to give 16.2 g of the compound identified as dihydrochloride in elemental analyzes. Performance: 100%. 1 H-NMR (as base) (500 MHz, CDCl 3) d: 7.45-6.70 (m, 9H), 3.84 (broad s, 0.7H), 3.55-2.8 (m, 4.3H), 2.78-2.75 (2xs, 3H), 2.7-2.5 (m, 3H), 2.4-1.6 (m, 14H), 1.5 (s, 4H), 1. 4 (s, 2H). 13 C-NMR (125 MHz, CDCl 3, 30 ° C) d: 176.9, 171.6, 143.0, 136.4, 132.4, 130.5, 128.3, 126.7, 64.6, 57.2, 56.0, 53.4, 50.8, 47.3, 41.7, 38.7, 34.2, 30.4, 29.5, 27.2, 25.8, 24.9. LC-MS: M + 1: 559.

Retention time: 6.98 (API) Example 4: synthesis of 1 '- [(3S) -4-fbenzoyl (methyl) amino] -3- (3,4-dichlorophenyl) -butyl-1 -? /,? / - dimethyl-4-pyrrolidin-1-ylpiperidine-4-carboxamide (compound of example 99); Here: synthesis of? /,? / - d -methyl-4-pyrrolidin-1-ylpiperidine-4-carboxamide as starting material 1-benzyl-4-f (4-chlorobutanoyl) aminol picperidine-4-carboxylic acid ethyl ester 78. 3 g (0.298 mol) of ethyl 4-amino-1-benzylpiperidine-4-carboxylate and 50 ml of pyridine (0.6 mol, 2 eq) were dissolved in 1 L of CH2Cl2. The mixture was cooled to 5 ° C and 0.37 ml of chlorobutyryl chloride (0.33 mol, 1.1 eq) dissolved in 200 ml of CH 2 Cl 2 were added dropwise. The mixture was stirred over the weekend at room temperature. 800 ml of a saturated solution of NaHCO 3 was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2 x 500 mL). The organic layer was washed with NaHCO3 (2 x 800 mL) and evaporated to dryness. The mixture was purified on silica (eluent: CH 2 Cl 2 / MeOH, 100/0 to 97/3 to 95/5, v / v). Yield: 113 g (~ quantitative yield) of a yellow semi-solid. Ethyl 1-benzyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxylate 12 g of sodium hydride (290 mmol, 1.2 eq) were suspended in 600 ml of THF To this suspension was added a gel of 88.5 g of 1-benzyl-4 - [(4-chlorobutanoyl) -amino] -piperidine-4-carboxylic acid ethyl ester (240 mmol, 1 eq) in 200 ml of THF. The mixture was stirred overnight at room temperature. The NMR analysis revealed a conversion of 60-70%. 5 g of extra sodium hydride (120 mmol, 0.5 eq) and 9 g (60 mmol, 0.3 eq.) Of sodium iodide were added, and the mixture was stirred for another day at room temperature. The NMR analysis now revealed a complete conversion. The reaction was quenched with 1 L of water. The mixture was extracted with ethyl acetate (3x 1 L). The organic layer was washed with 500 ml of a saturated solution of sodium chloride in water. The combined aqueous layers were extracted with dichloromethane (2x 1 L). The combined organic layers were evaporated to dryness. The crude mixture was further purified on silica (eluent: CH 2 Cl 2 / MeOH, 100/0 to 95/5, v / v) to provide 68.4 g of the target compound (207 mmol, 67%) as a pale yellow solid. 1-benzyl -? /,? / - dimethyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxamide 65 g (200 mmol, 1 eq) of ethyl 1-benzyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxylate were dissolved in 600 ml of THF and 400 ml of 1 M NaOH was added. The mixture was stirred overnight at reflux. Analysis by CCF revealed a non-complete conversion. 100 ml of extra 1 M NaOH was added and the mixture was stirred at reflux for another 2.5 h. The mixture was cooled to room temperature and diluted with 500 ml of water. The mixture was extracted with CH2Cl2 (2 x 500 mL). The aqueous layer was cooled and neutralized with concentrated HCl HCl (ca. 20 ml). The mixture was concentrated in vacuo to dryness. This crude mixture was suspended in 1 L of dichloromethane. HCl salt of dimethylamine (21.9 g, 270 mmol, 1.35 eq), TBTU (86.7 g, 270 mmol, 1.35 eq) and triethylamine (138 ml, 1.0 mol, 5 eq) were added. The mixture was stirred overnight at room temperature. The mixture was diluted with CH2Cl2 (500 mL) and washed with water (500 mL), NaHCO3 (500 mL), water and a saturated solution of sodium chloride in water (250 mL). The mixture was evaporated to dryness. The crude mixture was purified on silica (eluent: CH 2 Cl 2 / MeOH, 95/5, v / v). Yield: 30.8 g of 1-benzyl-N, N-dimethyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxamide (93.5 mmol, 52%) as a pale yellow solid. ? /.? / - dimethyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxamide Benzyl-N, N -dimethyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxamide (29 g, 88 mmol) was dissolved in tera-butanol / water (600 ml, 9/1, v / v). ). Pd-C (6 g, 10%, wet) was added and the mixture was stirred under a hydrogen atmosphere (5 bar) at 50 ° C for 16 h. The NMR analysis revealed a complete conversion. The Pd-C was separated by filtration over celite. The celite crop was washed with tert-butanol / water (100 mL, 9/1, v / v). The volatile components were removed by evaporation in vacuo. The crude mixture was further purified on silica (eluent: CH2Cl2 / 3 N ammonia in methanol, 95/5 to 90/10, v / v). The appropriate fractions were pooled and concentrated to dryness. Yield: 18 g (75 mmol, 86%) as a white solid. ? /.? / - dimethyl-4-pyrrolidin-1-ylpiperidine-4-carboxamide To the suspension of 1 g (4.2 mmol) of N, N-dimethyl-4- (2-oxopyrrolidin-1-yl) -piperidine-4-carboxamide in 50 ml of absolute tetrahydrofuran was added dropwise 1.8 ml of Redal ( bis- (2-methoxyethoxy) -diohydroaluminate sodium) (3.5 M / toluene, 6.3 mmol). The resulting solution was stirred vigorously for 4 h at room temperature, then the reaction was quenched by the addition of 20 g of NaF, followed by 5 ml of an aqueous solution of 80% tetrahydrofuran. The resulting suspension was stirred for another hour, then the solids were filtered off, washed gently with 2 x 50 tetrahydrofuran and the organic phase was evaporated under reduced pressure. The crude amine was further purified by column chromatography on silica gel (acetonitrile 6.25: 25% aqueous ammonia 1) to yield a pale yellow oil which crystallizes slowly upon standing (330 mg, 35%). Melting point: 150 ° C. Synthesis of 1 - [(3S) -4-fbenzoyl (methyl) amino] -3- (3,4-dichloropheniD-butyl1 -? /.? / - dimethyl-4-pyrrolidin-1-ylpiperidine-4-carboxamide (compound of example To a suspension of 150 mg (0.0428 mmol) of the aldehyde of Example 1, 96 mg (0.0428 mmol) of N, N-dimethyl-4-pyrrolidin-1-ylpiperidine-4-carboxamide and 0. 5 g of sodium acetate in 21 ml of THF at room temperature under stirring were added 0.05 ml of acetic acid and the mixture was stirred for 5 hours at room temperature. To the mixture were added in portions 0.13 g (0.062 mmol) of sodium triacetoxyborohydride, and the mixture was further stirred at room temperature for 15 hours. The mixture was concentrated to dryness in vacuo and re-dissolved in 6 ml of ethyl acetate, 10 ml of MTBE and 0.12 g of KOH dissolved in 5 ml of water. The organic phase was washed with sodium hydrogen carbonate until pH 5-6 and 3 times with 10 ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness. The crude amine was further purified by chromatography on Example 6: Synthesis of (2S) -1'-((3S) -4-r-benzoyl (methyl) amino-3- (3,4-dichloro-phenyl) -butyl] -? /,? / - dimethyl-1 , 4'-bipiperidine-2-carboxamide (composed of example 100 in SS configuration) See procedure of example 5. Instead of L-picpecolic acid, D-pipecolic acid is used, providing 1267 g of the white crystalline amine salt (2S) -1 '- [(3S) -4- [benzoyl (methyl) amino] -3- (3,4-dichloro-pheny!) butyl] -? /,? / - dimethyl-1,4'-bipiperidine-2-carboxamide and after the subsequent steps including purification (ethyl acetate 10: methanol 1: triethylamine 1; Rf = 0.35) to 69 mg of a colorless amorphous foam (28%). [a] 22D = -16.2 °, c = 1, CHCI3. 1 H-NMR (500 MHz, CDCl 3) d: 7.45-7.3 (m, 4.5H), 7.25-7.0 (m, 2.8H), 6.9, 6.75 (2x wide, 0.65H), 3.85 (wide m, 0.65H) , 3.6-3.4 (m, 1 H), 3.55 (m, 1 H), 3.23 (broad s, 3H), 3.0 (m, 2H), 2.95 (s, 3H), 2.68 (m, 2H), 2.4 ( m, 1 H), 2.2 (dt, J = 11.0, 2.4 Hz, 1 H), 2.18 (m, 1 H), 2.0-1.3 (m, 14H), 1.25 (m, 1 H). 13 C-NMR (125 MHz, CDCl 3) d: 173.1, 171.7, 142.8, 136.0, 132.5, 130.6, 130.2, 129.5, 128.4, 127.2, 126.7, 63.8, 58.7, 56.0, 54.1, 53.4, 53.2, 45.5, 42.5, 41.5 , 38.9, 36.8, 36.2, 34.5, 33.7, 30.7, 30.2, 28.9, 25.7, 24.2, 23.8. LC-MS: M + 1 = 573. Retention time: 4.73 min (API); Example 7: synthesis of 1 '- [(3S) -4- [benzoyl (methyl) amino] -3- (3,4- column over silica gel (ethyl acetate 10: triethylamine 1; Rf = 0.35) giving 109 mg of a colorless amorphous foam (45%). 1 H-NMR (500 MHz, CDCl 3) d: 7.45-7.25 (m, 4.5H), 7.25-7.0 (m, 3H), 6.9, 6.75 (2 xs wide, 0.6H), 3.85 (wide m, 0.6H) , 3.51 (broad dd, J = 12.5, 10.1 Hz, 1 H), 3.5-2.75 (m, 9 H), 2.7 (broad s, 2H), 2.6 (wide s, 4H), 2.4-1.7 (m, 9H ), 1. 65 (broad s, 4H). 13 C-NMR (125 MHz, CDCl 3) d: 173.3, 171.5, 142.9, 136.4, 130.5, 130.2, 129.5, 128.4, 127.3, 126.8, 63.2, 56.1, 55.8, 53.3, 51.8, 51.3, 45.0, 42.5, 41.7, 38.8 , 37.9, 30.6, 28.0, 24.1. LC-MS: M + 1: 559. Retention time: 5.44 min (API); Example 5: Synthesis of (2R) -1 '- [(3S) -4- [benzoyl (methyl) amino-3-3- (3,4-dichloro-phenyl) -butyl-1-α /, / V-dimethyl- 1,4'-bipiperidine-2-carboxamide (example compound 100 in RS configuration) 1 g (7.75 mmol) of L-pipecolic acid and 1.6 g (8.0 mmol) of N-Boc-piperidin-4-one were dissolved in 20 ml of dichloromethane. To this solution, 0.48 ml of acetic acid was added and, after 30 min, 3.27 g (2 eq) of sodium triacetoxyborohydride was added. The resulting suspension was stirred for 24 h at room temperature. The reaction mixture was diluted with 30 ml of a saturated solution of sodium chloride in water and the product was extracted with water. x 20 ml of dichloromethane. The organic phase was dried over Na 2 SO and evaporated under reduced pressure to provide 2.4 g of [1, 4 '] - bipiperidinyl-2,1'-dicarboxylic acid 1'-tert-butyl ester. 2.4 g (7.7 mmol) of [1, 4'-bipiperidinyl-2,1'-dicarboxylic acid 1'-tert-butyl ester was dissolved in 20 ml of dichloromethane and 8 ml (2M / THF, 16 ml) were added. mmol) of dimethylamine, 1.75 ml (16 mmol) of N-methyl-morpholine and 2.1 g (16 mmol) of N-hydroxymethylbenzotriazole. Finally, 3 g (16 mmol) of EDC * HCl (ethyl-n '- (3-dimethylaminopropyl) -carbodiimide HCl salt) were added and the reaction mixture was stirred for 20 h at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with 2 x 20 ml of K2C03 / 10% water solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude amide was further purified by column chromatography on silica gel (ethyl acetate 2: ethanol 1, Rf = 0.45) yielding 1.4 g of 2-dimethylcarbamoyl- [1,4 '] -bipiperidinyl tert-butyl ester. -1 '-Coloryl solid colorless (53%). [a] 22D = + 47 °, c = 1, MeOH. 1.4 g (4.13 mmol) of 2-dimethylcarbamoyl- [1, 4 '] - biphenylperidyl-1'-carboxylic acid tert-butyl ester were dissolved in 1 ml of dichloromethane and then added. 10 ml of 6M HCl / isopropanol. The reaction mixture was stirred at room temperature for 3 h, at which time the product crystallized in the reaction medium. The suspension was diluted with 50 ml of MTBE. it was allowed to stir for a further 30 minutes, then filtered and washed with MTBE. The solid was dried under high vacuum for 1 h to remove traces of volatile materials, yielding 1.17 g of [1,4 '] - bipiperidinyl-2-carboxylic acid dimethylamide as a white powder (91%).

To a suspension of 150 mg of the aldehyde of Example 1 (0.0428 mmol), 135 mg (0.0428 mmol) of [1,4'-bipiperidinyl-2-carboxylic acid dimethylamide and 0.5 g of sodium acetate in 21 ml of THF a At room temperature under stirring, 0.05 ml of acetic acid was added and the mixture was stirred for 5 hours at room temperature. To the mixture were added in portions 0.13 g (0.062 mmol) of sodium triacetoxyborohydride, and the mixture was further stirred at room temperature for 15 hours. The mixture was concentrated to dryness in vacuo and redissolved in 6 ml of ethyl acetate, 10 ml of MTBE and 0.12 g of KOH dissolved in 5 ml of water. The organic phase was washed with sodium hydrogen carbonate until pH 5-6 and 3 times with 10 ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness. The crude amine was further purified by column chromatography on silica gel (ethyl acetate 10: methanol 1: triethylamine 1; Rf = 0.35) to give 121 mg of a colorless amorphous foam (49%). [a] 22D = -46.5 °: c = 1, CHCl3. 1 H-NMR (500 MHz, CDCl 3) d: 7.45-7.3 (m, 4.5H), 7.25-7.0 (m, 2.8H), 6.9, 6.75 (2x wide, 0.65H), 3.85 (wide m, 0.65H) , 3.6-3.4 (m, 1 H), 3.55 (dd, J = 13.1, 9.5 Hz, 1 H), 3.25 (broad s, 3H), 3.0 (m, 2H), 2.9 (s, 3H), 2.75 (m, 2H), 2 , 6 (s wide, 2H), 2.4 (m, 1 H), 2.2 (dt, J = 11.0, 2.4 Hz, 1 H), 2.18 (m, 1 H), 2.0-1.3 (m, 14H), 1.25 (m, 1 H). 13 C-NMR (125 MHz, CDCl 3) d: 173.1, 171.6, 142.9, 136.4, 132.7, 132.5, 130.5, 130.2, 129.5, 128.4, 127.2, 126.7, 63.9, 58.7, 55.9, 53.8, 53.6, 53.4, 45.5, 42.3 , 41.4, 38.8, 36.8, 36.2, 34.5, 33.5, 30.8, 30.3, 28.9, 25.8, 24.3, 23.9. LC-MS: M + 1 = 573. Retention time: 4.73 min (API). dichloro-phenyl) -butip-? /,? / - dimethyl-1,4'-bipiperidine-2'-carboxamide (example compound 100) See the procedure of Example 5. Instead of L-pipecolic acid or D-pipecolic acid, (DL) -pipecolic acid is used, providing 1,267 g of the white crystalline amine salt (2) -1 '- [(3S) - 4- [benzoyl (methyl) amino] -3- (3,4-dichloro-phenyl) butyl] -? /,? / - dimethyl-1,4'-bipiperidine-2-carboxamide and after the consequent steps including purification (ethyl acetate 10: methanol 1: triethylamine 1; Rf = 0.35) to 69 mg of a colorless amorphous foam (28%). [a] 22D = -16.2 °, c = 1, CHCI3. 1 H-NMR (500 MHz, CDCl 3) d: 7.45-7.3 (m, 4.5H), 7.25-7.0 (m, 2.8H), 6.9, 6.75 (2x wide, 0.65H), 3.85 (wide m, 0.65H) , 3.6-3.4 (m, 1 H), 3.55 (m, 1 H), 3.23 (broad s, 3H), 3.0 (m, 2H), 2.95 (s, 3H), 2.68 (m, 2H), 2.4 ( m, 1 H), 2.2 (dt, J = 11.0, 2.4 Hz, 1 H), 2.18 (m, 1 H), 2.0-1.3 (m, 14H), 1.25 (m, 1H). 13 C-NMR (125 MHz, CDCl 3) d: 173.1, 171.7, 142.8, 136.0, 132.5, 130.6, 130.2, 129.5, 128.4, 127.2, 126.7, 63.8, 58.7, 56.0, 54.1, 53.4, 53.2, 45.5, 42.5, 41.5 , 38.9, 36.8, 36.2, 34.5, 33.7, 30.7, 30.2, 28.9, 25.7, 24.2, 23.8. LC-MS: M + 1 = 573. Retention time: 4.73 min (API); Example 8: synthesis of? / - [(2S) -2- (3,4-dichlorophenin-4- (4- (1-((dimethylamino) -carbonyl] -cyclohexyl) piperazine-1 - il) butl] -? / - methylbenzamide (composed of example 96); Here: synthesis ge 1 - (4-benzylpiperazin-1 -yl) -? /,? / - dimethylcyclohexanecarboxamide as starting material 7. 9 g (0.0262 mol) of 1- (4-benzylpiperazin-1-yl) -cyclohexanecarboxamide (known from WO0058292) in 120 ml of anhydrous THF were added dropwise at room temperature with stirring to a suspension of 2.83. g (0.071 mol) of 60% sodium hydride in oil in 120 ml of anhydrous THF under nitrogen. The mixture was then heated to 60 ° C for 2 hours under stirring. After cooling the reaction mixture to room temperature, a solution of 6.33 g of methyl iodide in 80 ml of anhydrous DMF was added at room temperature and the reaction mixture was stirred additionally for 5 days. The reaction mixture was then poured into 500 g of ice water and the product was extracted with 500 ml of MTBE. The organic layer was recovered and washed with 500 ml of a saturated solution of sodium chloride in water. The organic phase was then dried over sodium sulfate and concentrated to dryness. The HPLC-MS shows the presence of the expected compound, as well as of its monomethylated analog. The mixture was then separated by column chromatography on silica gel with n-hexane: 1 / ethyl acetate 9 to provide 3.2 g of the expected compound (yield: 38%). Here: synthesis of? /,? / - dimethyl-1-piperazin-1-ylcyclohexane-carboxamide as starting material 3. 2 g (0.0097 mol) of the 1- (4-benzylpiperazin-1-yl) -? /,? / - dimethylcyclohexane-carboxamide were dissolved in 100 ml of ethanol and 0.7 ml of acetyl chloride was added. Subsequently, 1 g of 10% palladium on charcoal was added and the suspension was hydrogenated at 3 bar at room temperature for 15 hours. The catalyst was removed by filtration and washed with 25 ml of ethanol. The solvent was then distilled off to give 2.6 g of N, N-dimethyl-1-piperazin-1-yl-cyclohexane-carboxamide in the form of a crystalline hydrochloride (yield: 97%). Melting point: 230-1 ° C. Synthesis of? / - f (2S) -2- (3,4-dichlorophenyl) -4- (4- (1-r (dimethylamino) -carbonyl] cyclohexyl) -piperazin-1-yl) butyl1 -? / - methylbenzamide (compound from example 96); To a suspension of 150 mg of the aldehyde of Example 1 (0.0428 mmol), 130 mg (0.0428 mmol) of N, N-dimethyl-1-piperazin-1-yl-cyclohexane-carboxamide hydrochloride and 0.5 g of sodium acetate in 21 ml of THF at room temperature under stirring were added with 0.05 ml of acid. acetic acid and the mixture was stirred for 5 hours at room temperature. To the mixture were added in portions 0.13 g (0.062 mmol) of sodium triacetoxyborohydride, and the mixture was further stirred at room temperature for 15 hours. The mixture was concentrated to dryness in vacuo and redissolved in 6 ml of ethyl acetate, ml of MTBE and 0.12 g of KOH dissolved in 5 ml of water. The organic phase was washed with sodium hydrogen carbonate until pH 5-6 and 3 times with 10 ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness. The crude amine was further purified by column chromatography on silica gel (ethyl acetate 10: methanol 1: triethylamine 1; Rf = 0. 35) by supplying 260 mg of a colorless amorphous foam (85%) in the form of d-hydrochloride. 1 H-NMR (as the hydrochloride) (500 MHz, CD 3 OD) d: 7.65-6.95 (m, 8H), 3.82 (m, 2H), 3.80-3.5 (m, 3H), 3.2-2.9 (m, 15H ), 2.8 (m, 2H), 2.5-1.1 (m, 12H). 13 C-NMR (125 MHz, CD 3 OD) d: 174.1, 142.7, 137.3, 133.8, 132.5, 132.1, 129.7, 129.1, 128.1, 127.7, 58.2, 56.0, 53.7, 51.7, 47.3, 42.1, 39.2, 28.5, 27. 1, 25.1. LC-MS: M + 1 (monoisotope): 585. Retention time: 5.22 min (API). Example 9: Synthesis of 1 - [(3S) -4- [benzoyl (methyl) aminol-3- (3,4-dichlorophenol) -butyl1-4-cyclohexyl-? /, / -dimethyl-piperidine-4'-carboxamide (compound from example 95) g (13.25 mmol) of 4-phenyl-4-piperidinecarboxylic acid tosylate salt were dissolved in 50 ml of dichloromethane, and then 3.75 ml (27 mmol) of triethylamine and 3.1 g (14 mmol) of bis-tert-butyloxycarbonate were added. . The reaction mixture was stirred for 16 h, then diluted with 100 ml of ethyl acetate and washed once with 50 ml of 10% aqueous acetic acid and 3 times with 50 ml of a saturated solution of sodium chloride in the reaction mixture. Water. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 3.97 g of white crystals of N-Boc-4-phenyl-4-piperidinecarboxylic acid (98%). 13 mmol of N-Boc-4-phenyl-4-piperidinecarboxylic acid were dissolved in 100 ml of ethanol and hydrogenated with hydrogen (6 bar) on Rh 5% / AI203 at 60 ° C for 20 h. After filtration and evaporation of the solvent, pure crystalline N-Boc-4-cyclohexyl-4-piperidinecarboxylic acid 4.0 g (100%) was isolated. Melting point: 156 ° C. 1 g (3.2 mmol) of N-Boc-4-cyclohexyl-4-piperidinecarboxylic acid was dissolved in 20 ml of dichloromethane and a drop of dimethylformamide was added.

To the resulting solution 0.29 ml (1.05 eq) of oxalyl chloride was added and the solution was stirred for 30 min. 3.2 ml of dimethylamine (2M / THF, 2 eq) and the mixture was stirred for an additional 30 minutes. The solution was diluted with 50 ml of ethyl acetate and washed with 2 x 20 ml of 10% aqueous potassium carbonate. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude amide was purified by column chromatography on silica gel (dichloromethane 20: acetone 1, Rf = 0.3), yielding 217 mg of N-Boc-4-cyclohexyl-4-piperidinecarboxylic acid dimethylamide in the form of an oil colorless (20%). 217 mg (0.64 mmol) of N-Boc-4-cyclohexyl-4-piperidine-carboxylic acid dimethylamide were dissolved in 0.5 ml of dichloromethane and then 2 ml of 6M HCl / isopropanol was added. The reaction mixture was stirred at room temperature for 3 h, at which time the product crystallized in the reaction medium. The suspension was diluted with 20 ml of MTBE, allowed to stir for an additional 30 minutes, and then filtered and washed with MTBE. The solid was dried under high vacuum for 1 h to remove traces of volatile materials, yielding 157 mg of 4-cyclohexyl-4-piperidinecarboxylic acid dimethylamide hydrochloride (90% strength) as a white powder. To a suspension of 95 mg (0.027 mmol) of the aldehyde of Example 1, 75 mg (0.0428 mmol) of 4-cyclohexyl-4-piperidinecarboxylic acid dimethylamide hydrochloride and 0.3 g of sodium acetate in 20 ml of THF at room temperature At room temperature under stirring, 0.03 ml of acetic acid was added and the mixture was stirred for 5 hours at room temperature. To the mixture was added in portions 0.1 g (0.045 mmol) of sodium triacetoxyborohydride, and the mixture was further stirred at room temperature for 15 hours. The mixture was concentrated to dryness in vacuo and redissolved in 6 ml of ethyl acetate, 10 ml of MTBE and 0.12 g of KOH dissolved in 5 ml of water. The phase organic was washed with sodium hydrogen carbonate until pH 5-6 and 3 times with 10 ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness. The crude amine was further purified by column chromatography on silica gel (ethyl acetate 10: triethylamine 1; Rf = 0.35) yielding 102 mg of a colorless amorphous foam (66%). 1 H-NMR (500 MHz, CDCl 3) d: 7.45-7.3 (m, 4.5H), 7.25-7.0 (m, 2.7H), 6.9, 6.75 (2x wide, 0.65H), 3.8 (m, 0.5H), 3.6-3.4 (m, 1.5H), 3.15 (m, 0.6H), 3.0 (s, 6H), 2.9-2.5 (m, 4H), 2.2 (m, 0.6H), 2.1 (broad d, J = 12.5 Hz, 2H), 2.05-1.8 (m, 4H), 1.78 (broad d, J = 11.6 Hz, 2H), 1.6, (m, 6H), 1.3-3.0 (m, 5H). 13 C-NMR (125 MHz, CDCl 3) d: 173.6, 170.5, 143.0, 135.4, 131.4, 129. 6, 129.5, 129.2, 128.4, 127.3, 126.5, 126.2, 125.7, 55.4, 52.3, 51.1, 50.6, 49.5, 42.7, 41.5, 40.6, 37.7, 32.5, 29.7, 29.7, 27.1, 26.2, 25.5. LC-MS: M + 1: 572. Retention time: 5.57 min (API); Example 11: synthesis of? / -. { (2S) -2- (3,4-Dichlorophenyl) -4- [4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) piperidin-1-in-butyl) -? / - methylbenzamide (compound of example 103) Here: synthesis of 1-benzyl-4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) piperidine as starting material 2. 34 ml (0.0132 mol) of N-benzylpiperidin-4-one, 4.4 ml (0.0527 mol) of pyrrolidine, 1.6 ml (0.02 mol) of chloroform and 38 mg of n-benzyltriethylammonium chloride were stirred at 5 ° C. To the stirred mixture and maintaining the temperature at 5 ° C, a solution of 2.6 g of sodium hydroxide in 5 ml of water was added dropwise. After 15 hours of stirring at 5 ° C, 50 ml of water was added and the organic material was extracted 3 times with 10 ml of methylene chloride. The organic phase was separated and washed twice with 30 ml of water. The organic phase was then separated, dried over sodium sulfate and concentrated to dryness, yielding 3426 g of an oily material showing the presence in NMR and MS of the expected compound. Purification: 3 g of the mixture were separated in MPLC over 112 g of SiO2 with n-hexane-ethyl ester 1: 1 as the eluent mixture, yielding 1.94 g of the expected compound as a white solid. (According to Lai, J. Org. Chem. 1980, page 3671). Here: synthesis of 4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) -piperidine as starting material 1. 9 g (0.00556 mol) of 1-benzyl-4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) -piperidine were dissolved in 200 ml of ethanol at 30 ° C and hydrogenated in the presence of 4 spatulas of 20% palladium hydroxide on charcoal (humidity of 60%) at 4 bars for 6 hours at 40 ° C. The catalyst was recovered by filtration and the solution was concentrated to dryness, yielding the expected debenzylated compound which was identified in NMR and MS and used without further purification. Synthesis of? / - ((2S) -2- (3,4-dichlorophenyl) -4-f4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) piperidin-1-yl butylWV-methylbenzamide (compound of example 103) To a suspension of 180 mg (0.51 mmol) of the example aldehyde 1180 mg (0.51 mmol) of 4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) -piperidine and 0.3 g of sodium acetate in 20 ml of THF at room temperature and with stirring were added 0.03 ml of acetic acid and the mixture was stirred for 5 hours at room temperature. To the mixture was added in portions 0.2 g (0.09 mmol) of triacetoxy boron sodium hydride, and the mixture was stirred additionally at room temperature for 15 hours. The mixture was concentrated to dryness in vacuo and redissolved in 6 ml of ethyl acetate, 10 ml of MTBE and 0.2 g of KOH dissolved in 5 ml of water. The organic phase was washed with sodium hydrogen carbonate until pH 5-6 and 3 times with 10 ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness. The crude amine was further purified by column chromatography on silica gel (ethyl acetate 10: triethylamine 1; Rf = 0.35) giving 236 mg of a colorless amorphous foam (79%). 1 H-NMR (as base) (500 MHz, CDCI3) d: 7.45-6.70 (m, 8H), 3.85 (m, 2H), 3.6-3.4 (m, 4H), 3.3-2.5 (m, 10H), 2.35-1.9 (m, 8H), 1.78 ( s, 4H), 1.67 (s, 4H). 13 C-NMR (125 MHz, CDCl 3) d: 172.4, 171.6, 143.0, 136.5, 132.4, 130.5, 129.4, 128.3, 127.3, 126.7, 62.9, 56.1, 53.3, 51.7, 51.1, 47.5, 45.1, 41.7, 38.7, 27.9 , 27.4, 24.0, 23.2. LC-MS: M + 1 (monoisotope): 585. Retention time: 5.85 min (API). Example 12: Synthesis of 3-cyano -? / - ((2S) -2- (3,4-dichlorophenyl) -4-r4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) piperidin-1 - il] butyl) - / -methyl-1-naphtamide (composed of example 102) Here: synthesis of 3-cyano-naphthalene-1-carboxylic acid [2S- (3,4-dichloro-phenyl) -4-oxo-butyl] -methyl-amide as starting material 12. 2 g of DMSO in 100 ml of dichloromethane are added dropwise to 7.3 g of oxalyl chloride in 100 ml of dichloromethane under nitrogen at -70 ° C with stirring. The resulting mixture was stirred for another 15 minutes before adding 20 g of [2S- (3,4-dichloro-phenyl) -4-hydroxy-butyl] -methyl-carbamic acid tert-butyl ester in 200 ml of dichloromethane . The mixture was stirred at -70 ° C for one hour before adding 40.3 ml of triethylamine in 50 ml of dichloromethane dropwise. The solution was stirred at -70 ° C for 15 minutes and then allowed to warm to room temperature. The solvent was removed and the residue was dissolved in 300 ml of toluene and 200 ml of ethyl acetate. The resulting solution was washed six times with 200 ml of a saturated NaCl solution in water, dried over sodium sulfate and concentrated to dryness to give 19.7 g of [2S- (3,4-dichloro-phenyl) - 3-cyano-naphthalene-1-carboxylic acid 4-oxo-butyl] -methyl-amide. Synthesis of 3-cyano- / V-. { (2S) -2- (3,4-Dichlorophenyl) -4- [4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) piperidin-1-yl] butyl) -? / - methyl-1 - naphthamide (composed of example 102): 253.8 mg (0.0006 mol) of 3-cyano-naphthalene-1-carboxylic acid [2S- (3,4-dichloro-phenyl) -4-oxo-butyl] -methyl-ida acid 150 mg (0.006 mol) of 4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) -piperidine and 72 mg (0.0012 mol) of acetic acid were dissolved in 20 ml of methylene chloride and stirred for 30 minutes at room temperature. Subsequently, 163.7 mg were added of sodium triacetoxyborohydride and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with 40 ml of ethyl acetate and the resulting phase was washed twice with 50 ml of an aqueous 10% potassium carbonate solution and once with 50 ml of a saturated sodium chloride solution. in water The organic phase was then separated and concentrated to dryness to give 280 mg of the title base as an amorphous solid. 1 H-NMR (500 MHz, CDCl 3) d: 8.24 (0.35H), 8.19 (0.65H), 7.97-6.50 (m, 8H), 4.4 (broad s, 0.65H), 3.85 (broad s, 2H), 3.7 -3.25 (m, 3.35H), 3.2 (s, m, 1H), 3.0-1.9 (m, 10H), 1.8 (s, 4H), 1.68 (s, 4H). 13 C-NMR (125 MHz, CDCl 3) d: 172.4, 172.3, 142.5, 136.5, 134.7, 132.4, 131.0, 130.6, 130.5, 130.1, 128.3, 127.5, 126.7, 125.2, 123.9, 118.4109.0, 63.0, 57.1, 56.0 , 53.3, 51.7, 51.1, 47.5, 45.1, 45.0, 41.7, 38.7, 37.7, 33.6, 31.6, 27.9, 27.4, 24.0. LC-MS: M + 1 (monoisotope): 573. Retention time: 7.90 min (API). Example 13: Synthesis of? / - ((2S) -2- (3,4-dichlorophenyl) -4- [4'-piperidin-1-ylcarbonyl) -1,4'-bipiperidin-1'-yl] butyl) -? / - methylbenzamide (compound of example 104) Here: synthesis of 1'-benzyl-4 '- (piperidin-1-alkylcarbonyl) -1,4'-bipiperidine as starting material l-benzyl-1-piperidine-1-carbonyl-1'-bipiperidine was obtained by condensing 2.34 ml (0.00132 mol) of N-benzylpiperidin-4-one, 5.3 ml (0.00536 mol) of piperidine, 1.6 ml ( 0.002 mol) of chloroform and 38 mg of benzyltriethylammonium chloride. A crude mixture of 4,445 g of an oily material was supplied (yield: 90%), 2 g of which were subsequently purified on preparative HPLC with a gradient of acetonitrile / water containing formic acid in 2 runs to deliver 678 mg of the product in the form of diformate after lyophilization of the fractions containing the expected pure compound. Here: synthesis of 4 '- (piperidin-1-ylcarbonyl) -1,4'-bipiperidine as starting material 576 mg of 1-benzyl-1-piperidin-1-ylcarbonyl-1,1-bipiperidine in the form of dicycloate was converted to the dihydrochloride, dissolved in 50 ml of ethanol and hydrogenated at 40 ° C for 4 days in the presence of 50 mg of ethanol. mg of 10% palladium on charcoal. The catalyst was separated by filtration and washed 3 times with 50 ml of ethanol. The organic phases were combined and concentrated to dryness to give 4 '- (piperidin-1-ylcarbonyl) -1,4'-bipiperidine in the form of a solid dihydrochloride.

Synthesis of ?/-. { (2S) -2- (3,4-Dichlorophenyl) -4- [4'-piperidin-1-ylcarbonyl) -1,4'-bipiperdin-1'-yl] butyl) -? / - methylbenzamide (compound of example 104) 127 mg (0.00036 mol) of the aldehyde of example 1160 mg (0.0036 mol) of 4, - (piperidin-1-ylcarbonyl) -1,4'-bipiperidine in the form of a solid dihydrochloride and 35 mg (0.0006 mol) of Acetic acid was dissolved in 20 ml of methylene chloride and stirred for 30 minutes at room temperature. Subsequently, 85 mg of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with 20 ml of ethyl acetate and the resulting phase was washed twice with 50 ml of an aqueous 10% potassium carbonate solution and once with 50 ml of a saturated sodium chloride solution. in water The organic phase was then separated and concentrated to dryness to give 206 mg of the title base as a colorless foam in the form of the hydrochloride (quantitative yield). 1 H-NMR (as hydrochloride) (500 MHz, CDCI 3 OD) d: 7.65-6.95 (m, 8H), 3.8 -3.55 (m, 8H), 3.35-3.25 (2xs, 3H), 3.2-2.4 (m , 13H), 2.35-2.15 (m, 2H), 1.95 (s, 4H), 1.7 (s, 2H), 1.62 (s, 4H). 13 C-NMR (125 MHz, CD3OD.) D: 174.1, 142.7, 137.3, 133.8, 132.5, 132.1, 129.7, 129.1, 128.1, 127.7, 58.2, 56.0, 53.7, 51.7, 47.3, 42.1, 39.2, 28.5, 27.1, 25.1.

LC-MS: M + 1 (monoisotope): 613. Retention time: 6.14 min (API). Example 13: synthesis of? / - ((2S) -2- (3,4-dichlorophenyl) -4-r4'-pyrrolidin-1-ylcarbonyl) -1,4'-bipiperidin-1'- l] butyl) -? / - methylbenzamide (compound of example 124.).

Here: synthesis of 1'-benzyl-1,4'-bipiperidine-4'-carboxamide as starting material 4. 5 g (52.8 mmol) of piperidine, 5 g (26.4 mmol) of N-benzyl-piperidin-4-one, 9.5 g (3 eq) of magnesium sulfate and 2.3 ml of N-dimethylacetamide were mixed together and then added 2.6 ml (1 eq) of 2-cyano-2-hydroxypropane. The resulting suspension was stirred for 48 h at 55 ° C, after which it solidifies a slurry. The crude product was mixed with 100 ml of water and 100 ml of ethyl acetate. The organic phase was washed with water (2 x 50 ml), dried over sodium sulphate and evaporated to give 7 g of crude aminonitrile. 1.3 g (3.6 mmol) of the resulting aminonitrile were dissolved in 15 ml of 90% strength by weight sulfuric acid and heated for 10 minutes at 100 ° C.

The resulting solution was poured onto ice and then basified to pH 9 with sodium hydroxide. Crude amine was extracted with ethyl acetate (3 x 30 mL), the organic phase was washed once with a saturated solution of sodium chloride in water, dried over sodium sulfate and evaporated. Yield 1 g (92%) of light yellow crystals of 1'-benzyl-1,4'-bipiperidine-4'-carboxamide. Here: synthesis of? /,? / - diallyl-1'-benzyl-1,4'-bipyperidine-4'-carboxamide as starting material 1. 75 g (5.83 mmol) of 1'-benzyl-1'-bipiperidine ^ '-carboxamide were dissolved in 10 ml of hexamethylphosphorotriamide. To this solution were added portionwise 466 mg (2 eq) of sodium hydride (60% in oil) and the suspension was stirred at 60 ° C for 2 hours. Then, the resulting solution was cooled to room temperature and 1 ml (2 eq) of allyl bromide was added over 6 hours through a syringe pump. After 24 h, the reaction was quenched by the addition of 10% aqueous ammonium chloride (50 mL) and the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The crude compound was further purified by column chromatography on silica gel (ethyl acetate 5: ethanol 1, Rf = 0.3), yielding 1 g (45%) of? /,? / - diallyl-1'-benzyl -1,4'-bipiperidine-4'-carboxamide desired. Here: synthesis of 1'-benzyl-4 '- (2,5-dihydro-1 / - / - pyrrol-1-ylcarbonyl) -1,4'-bipiperidine as starting material 1 g (2.6 mmol) of? ,? - diallyl-1'-benzyl-1, 4'-bipiperidine-4'-carboxamide was dissolved in 50 ml of dichloromethane and to the resulting refluxing solution was added portionwise of Grubbs-1 catalyst (1 g, 50 mol%) over 36 hours. The solvent was evaporated and the product was purified by column chromatography on silica gel (ethyl acetate, Rf = 0.35), yielding 640 mg (70%) of r-benzyl-4 '- (2,5-dihydro-1H) -pyrrol-1-ylcarbonyl) -1,4'-bipiperidine pure. Here: synthesis of 4 '- (pyrrolidin-1-ylcarbonyl) -1,4'-bipiperidine as starting material 0. 64 g (1.81 mmol) of 1'-benzyl-4 '- (2,5-dihydro-1H-pyrrol-1-ylcarbonyl) -1,4'-bipiperidine were dissolved in 70 ml of ethanol and they added 200 mg of 20% Pd (OH) on carbon (60% humidity). The compound was hydrogenated with hydrogen under a pressure of 5 bar. After 4 hours, the catalyst was removed by filtration and the solvent was evaporated under reduced pressure, yielding 470 mg (99%) of a blue-grayish crystalline powder. Melting point: 144 ° C. Synthesis of? - ((2S) -2- (3,4-dichlorophenyl) -4- [4 '- (pyrrolidin-1-ylcarbonyl) - 1,4'-bipiperidin-1 '-yl-1-butyl) -? / - methylbenzamide (composed of example 124) 150 mg (0.005 mol) of the aldehyde of the example 1120 mg (0.005 mol) of 4 '- (pyrrolidin-1-ylcarbonyl) -1,4'-piperidine and 35 mg (0.0006 mol) of acetic acid were dissolved in 20 ml of methylene chloride and stirred for 30 minutes at room temperature. Subsequently, 85 mg of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with 20 ml of ethyl acetate and the resulting phase was washed twice with 50 ml of an aqueous 10% potassium carbonate solution and once with 50 ml of a saturated sodium chloride solution. in water The organic phase was then separated and concentrated to dryness to give the title compound. After purification, 171 mg of? / - were isolated. { (2S) -2- (3,4-Dichlorophenyl) -4- [4, - (pyrrolidin-1-ylcarbonyl) -1,4'-bipiperidin-1-yl] butyl} -? / - methylbenzamide (66%). 1 H-NMR (500 MHz, CDCl 3) d: 7.45-7.3 (m, 4.6H), 7.25-7.0 (m, 2.8H), 6.9, 6.75 (2x wide, 0.65H), 4.1-3.7 (m, 2H) , 3.6-3.4 (m, 3.65H), 3.15 (s wide, 0.65H), 3.0 (s wide, 1 H), 2.9-2.6 (m, 5H), 2.46 (s, 4H), 2.3-1.85 (m , 8H), 1.75 (broad s, 7H), 1.5 (m, 4H), 1.4 (m, 2H). 13 C-NMR (125 MHz, CDCl 3) d: 172.4, 171.6, 142.9, 136.4, 132.4, 130.5, 130.2, 129.4, 128.3, 127.2, 126.7, 66.4, 57.1, 56.1, 55.7, 53.3, 51.6, 51.1, 47. 8, 47.2, 42.5, 41.6, 38.7, 33.6, 30.9, 27.4, 27.1, 26.9, 25.1, 23.2. LC-MS: M + 1 = 598. Retention time: 5.82 min (API). Example 14: Alternative synthesis of 1 '-f (3S) -4- [benzoyl (methyl) aminol-3- (3,4-dichlorophenyl) -butyl-1 -? / - ethyl-N-methyl-1,4'-bipiperidine -4'-carboxamide (compound of example 95) 100 mg (0.158 mmol) of 1 '- [4- (benzoyl-methyl-amine) -3- (3,4-dichloro-phenyl) -butyl] - [1.4'] bipiperidinyl-4 methylamide The carboxylic acid was dissolved in 1 ml of absolute DMSO and then 21 mg (0.19 mmol) of potassium tert-butylate were added under an inert atmosphere. The resulting solution was stirred at room temperature for 1 h, then 25 mg (0.16 mmol) of ethyl iodide was added and the reaction mixture was stirred for an additional 24 h at room temperature. The reaction mixture was diluted with 10 ml of 10% aqueous NH CI solution and the product was extracted with ethyl acetate (3 x 10 ml). The organic phase was dried over Na 2 SO and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate 5: methanol 1, Rf = 0.25) to provide a colorless foam (31 mg, 30%). 1 H-NMR (500 MHz, CDCl 3) d: 7.3 (m, 4.5H), 7.25-7.0 (m, 3H), 6.9, 6. 7 (2x wide, 0.6H), 3.9 (broad s, 0.6H), 3.5 (dd, J = 12.97, 9.92 Hz, 1 H), 3.4 (m, 3.5 H), 3.2 (wide s, 1 H), 3.0-2.7 (m, 3H), 2.7 (s, 3H), 2.5 (s wide, 4H), 2.4-1.6 (m, 10H), 1.5 (s, 4H), 1.4 (s, 2H), 1.1 (s) width, 3H). 13 C-NMR (125 MHz, CDCl 3) d: 173.0, 172.0, 136.3, 130.6, 130.2, 129.5, 128.4, 127.2, 126.8, 66.4, 56.2, 55.9, 53.4, 51.7, 51.1, 50.6, 47.3, 44.6, 44. 1, 42.5, 41.6, 41.1, 38.8, 36.0, 34.0, 33.5, 30.2, 29.7, 29.4, 26.9, 25.1, 11.7. LC-MS: M + 1 = 587. Retention time: 5.59 min (API). Example 14: Synthesis of 4- ( { [(2S) -2- (3,4-dichlorophenyl) -4- (4 '- [(dimethylamino) -carbonyl] -1,4'-bipiperidin-1 '-yl) butyl] (methyl) amino) carbonyl) phenyl (compound of example 5) Here: synthesis of carbamate [(2S) -2- (3,4-dichlorophenyl) -4-. { 4 '- [(dimethylamino) -carbonin-1,4'-bipiperidin-1'-yl) butyl methyl tere-butyl as starting material To a suspension of 4 g (0.0115 mol) of [2- (3,4-dichloro-phenyl) -4-oxo-butyl] -methyl-carbamic acid tert-butyl ester, 4.35 g (0.0139 mol) of the hydrochloride of piperidinopiperidinacetamide, [1, 4 '] bipperidinyl-4'-carboxylic acid dimethylamide and 2 g of sodium acetate in 200 ml of THF were added 1.5 ml of acetic acid. The reaction mixture was stirred for 4 hours at room temperature. To the reaction mixture were then added in portions 4.88 g (0.0231 mol) of sodium triacetoxyborohydride and the solution was stirred for 15 hours at room temperature and, subsequently, concentrated to dryness. The remaining material was dissolved in 100 ml of MTBE and 5 g of potassium hydroxide in 50 ml of water. The separated organic layer was then washed three times with 50 ml of water, dried over sodium sulfate and concentrated to give 6.06 g of a foam which was used in the next step without further purification. Yield: 92% Here: synthesis of 1 '- [(3S) -3- (3,4-dichlorophenyl) -4- (methylamino) butyl-? /,? / - dimethyl-1,4'-bipiperidine-4' -carboxamide as starting material 6 g (0.0105 mol) of [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1, 4 '] - bipiperidinyl-1'-yl) butyl tert-butyl ester - butyl] -methyl-carbamic acid were dissolved in 10 ml of methylene chloride and 40 ml of 5N solution of HCl in isopropanol (0.2 mol) at room temperature. A precipitate of 1'- [(3S) -3- (3,4-dichlorophenyl) -4- (methylamino) butyl] -? /,? / - dimethyl-1,4'-bipiperdin-4'- resulted carboxamide in the form of hydrochloride, and the mixture was stirred for 15 hours until the reaction was complete. The mixture was added dropwise in 150 ml of MTBE and further stirred for 1 hour at room temperature. The precipitate was separated by filtration, washed 3 times with 10 ml of MTBE and the solid obtained was dried under vacuum at 60 ° C to deliver 4.1 g of 1 '- [(3S) -3- (3,4- dichlorophenyl) -4- (methylamino) butyl] -? /,? / - dimethyl-1,4'-bipiperidine-4'-carboxamide in the form of trihydrochloride. Performance: 67%. Optical rotation: -2.0 ° (c = 1% in methanol) Here: synthesis of 4- ( { [(2S) -2- (3,4-dichlorophenyl) -4- { 4 '- [(? /.?/- dimethyl amino) -carbonipi, 4'-bipiperidin-1 '-yl) butyl1 (methyl) amino) carbonyl) phenyl 220 mg (0.00038 mol) of 1 '- [(3S) -3- (3,4-dichlorophenyl) -4- (methylamino) butyl] -? / ,? -dimethyl-1, 4'-bipiperidine-4'-carboxamide were dissolved in 20 ml of methylene chloride in the presence of 200 μl of triethylamine under stirring to the room temperature. To the reaction mixture was added dropwise, at room temperature, a solution of 98 mg of 4-acetoxybenzoyl chloride in 20 ml of methylene chloride and, subsequently, 200 μl of triethylamine was added. The reaction mixture was stirred for 15 hours at room temperature and concentrated in vacuo. The residue was dissolved in 50 ml of ethyl acetate and 30 ml of MTBE in the presence of 200 mg of potassium hydroxide dissolved in 20 ml of water. The organic phase was separated and washed 4 times with 20 ml of water. The organic layer was recovered, dried over sodium sulfate and concentrated to dryness to give 240 mg (quantitative yield) of 4- ( { [(2S) -2- (3,4-dichlorophenyl) -4 acetate. -. {4 '- [(dimethylamino) carbonyl] -1,4'-bipiperidin-1'-yl.} Butyl] (methyl) amino} carbonyl) phenyl in the form of a glassy material. 1 H-NMR (as base) (500 MHz, CDCl 3) d: 7.45-7.1 (m, 3H), 7.0, 6.8 (2 xs wide, 0.7H), 3.82 (s broad, 0.7H), 3.55 (dd, 1 H), 3.5-3.2 (m, 4 H), 3.1 (broad s, 0.7H), 3.0 (m, 2H), 2.95-2.90 (2xs, 3H), 2.8-2.5 (m, 4.5H), 2.3 ( s, 3H), 2.25-1.6 (m, 12H), 1.5 (s, 4H), 1.4 (s, 2H). 13 C-NMR (125 MHz, CDCl 3) d: 170.7, 168.2, 150.7, 131, 7., 121, 5, 120.9, 66.1, 55.2, 56.1, 52, 6, 51, 7, 50.9, 50.4, 46.6, 40.9, 38.0, 36.9, 29.9, 26.2, 24.4, 20.4. LC-MS: M + 1 (monoisotope): 631. Retention time: 7.78 min (API). Example 15: Synthesis of 1 '- ((3S) -3- (3,4-dichlorophenyl) -4-f (4-hydroxybenzoyl) - (methyl) aminol butyl) -? /,? / - dimethyl-1, 4 '-piperidine-4'-carboxamide (composed of example 6) 170 mg (0.00027 mol) of 4- ( { [(2S) -2- (3,4-dichlorophenyl) -4-. {4 '- [(dimethylammon) -carbonyl] -1, 4'-bipperidin-1, -l.} Butyl] (methyl) amino} carbonyl) phenyl were dissolved in 30 ml of methanol in the presence of 300 mg of potassium hydroxide at room temperature and stirred for 20 hours. The solution was then concentrated to dryness and dissolved in 50 ml of ethyl acetate, 40 ml of MTBE and a solution of 2 g of ammonium chloride in 20 ml of water until reaching pH 7. The organic phase was separated, washed 3 times with 20 ml of water, dried over sodium sulfate, concentrated in vacuo to give 102 mg of 1%. { (3S) -3- (3,4-Dichlorophenyl) -4 - [(4-hydroxybenzoyl) (methyl) amino] -butyl} -? /,? / - dimethyl-1,4'-bipiperidine-4'-carboxamide in the form of a glassy compound (yield: 64%). 1 H-NMR (as base) (500 MHz, CDCl 3) d: 7.40-6.70 (m, 7H), (2x wide, 0.7H), 3.88 (broad s, 0.7H), 3.45 (dd, 1 H), 3.5 -3.25 (m, 4 H), 3.2 (s wide, 0. 7 H), 3.0 (m, 2H), 2.95-2.90 (2xs, 3H), 2.8-2.5 (m, 4.5H), 2.4-1.6 (m, 12H), 1.5 (s, 4H), 1.4 (s, 2H). 13 C-NMR (125 MHz, CDCl 3) d: 173.5, 172.8, 172.4, 160.1, 158.8, 132. 9, 131 .56, 131.4, 130.9, 129.8, 127.1, 70.6, 65.9, 55.6, 53.4, 51.7, 47.3, 38. 7, 37.8, 31.9, 26.7, 26.0, 24.9 LC-MS: M + 1 (monoisotope): 589.

Retention time: 7.06 min (API). Example 16: Synthesis of 1 '- [(3S) -4- [benzoyl (methyl) aminol-3-phenyl-1-yl], [beta] / - dimethyl-1,4'-bipiperidine-4'-carboxamide 700 mg (0.00108 mol) of 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4-methylamide dihydrochloride The carboxylic acid was dissolved in 100 ml of ethanol at room temperature. To the solution were added 50 ml of water and 560 mg of potassium hydroxide. The solution was hydrogenated for 5 days at room temperature in the presence of 5 spatulas of 10% palladium on charcoal at 4 bars. The solution was recovered after filtration and separation of the catalyst, concentrated to dryness and subsequently dissolved in 60 ml of MTBE. The organic phase was washed 3 times with 10 ml of water, separated, dried over sodium sulfate and concentrated to dryness to give the title product as 405 mg of an oily material (yield: 74%). 390 mg of the base was dissolved in 2 ml of ethanol at 40 ° C and 330 μl of 5N HCl in IPA was added under stirring to give a solution to which 20 ml of MTBE was added to deliver a precipitate. After heating the solution to 50 ° C, the suspension was cooled to room temperature. The precipitate was recovered by filtration, washed twice with 10 ml of methanol, dissolved in methanol, whose concentration to dryness yielded 435 mg (98% yield) of a dihydrochloride. colorless spongy 1 H-NMR (as base) (500 MHz, CDCl 3) d: 7.40-6.85 (m, 10H), 3.87 (broad s, 0.7H), 3.58 (dd, 0.7H), 3.5-3.25 (m, 4.4 H) , 3.1 (broad s, 0.7 H), 2.96 (m, 2H), 2.95-2.85 (broad s, 3H), 2.85-2.45 (m, 4.5H), 2.3-1.6 (m, 12H), 1.51 (s, 4H), 1.41 (s, 2H). 13 C-NMR (125 MHz, CDCl 3) d: 173.5, 171.5, 142.4, 136.8, 129.2, 128.7, 128.5, 128.2, 128.0, 126.7, 66.9, 57.6, 56.4, 53.4, 51.8, 47.3, 42.4, 38.5, 37.7, 33.6, 31.1, 26.9, 25.1. LC-MS: M + 1 (monoisotope): 505. Retention time: 4.94 min (API). Examples 17 to 36 Compounds 105 to 123 were obtained by reductive amination as outlined in process (a). An aldehyde is reductively aminated with an amine to provide the compound of formula I, examples 105 to 123 Synthesis of? / - f (2S) -4-. { 4 - [(cyclopropylmethyl) (propionyl) -aminol pperidin-1-yl) -2- (34-dichlorophenyl) butyl] -? -methylbenzamide (composed of example 105) To a mixture of 105 mg (0.3 mmol) of N- [2- (3,4-dichloro-phenyl) -4-oxo-butyl] -N-methyl-benzamide (compound II), 70 mg (0.33 mmol) of N- (cyclopropylmethyl) -N-picperidin-4-ylpropanamide (compound III) and 37 mg (0.45 mmmol) of sodium acetate in 6 ml of THF at room temperature and under stirring were added in 0.03 ml (0.51 mmol) of acetic acid. After stirring for 0.5 h, 127 mg (0.6 mmol) of sodium triacetoxyborohydride were added to this mixture. After stirring for another 15 h, the mixture was concentrated in vacuo to dryness and redissolved in 20 ml of dichloromethane. The organic solution was washed three times with potassium hydrogen carbonate and then concentrated over sodium sulfate. After filtration, the roganic phase was concentrated in vacuo to dryness. The crude product was pued by column chromatography on silica gel using ethyl acetate / ethanol as eluents (100/0 to 80/20 v / v), yielding 93 mg of a colorless oil. The following compounds were prepared according to the described reductive amination procedure: N - [(2S) -2- (3,4-dichlorophenol) -4-. { 4- [isopropyl (propionyl) amino] piperidin-1-yl} butyl] -N-methylbenzamide (example of compound 106); N - [(2S) -2- (3,4-dichlorophenyl) -4-. { 4- [phenyl (propionyl) amino] piperidin-1-yl} butyl] -N-methylbenzamide (example of compound 107); N - [(2S) -4-. { 4- [butyl (propionyl) amino] piperidn-1-yl} -2- (3,4-dichloro-phenyl) butyl] -N-methylbenzamide (example of compound 108); N - [(2S) -4-. { 4- [buty1- (cyclopropylcarbonyl) amino] pyridin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide (example of compound 109); N - [(2S) -4-. { 4- [butyl (cyclohexylcarbonyl) -amino] piperidin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-5-methylbenzamide (example of compound 110); N - [(2S) -4-. { 4- [benzoyl (butyl) amino] piperidin-1-yl} -2- (3,4-dichloro-phenyl) butyl] - N -methylbenzamide (example of compound 111); N - [(2S) -2- (3,4-dichlorophenyl) -4-. { 4 - [(4-methoxybutyl) (propionyl) amino] piperidin-1-yl} butyl] -N-methylbenzamide (example of compound 112); N - [(2S) -4-. { 4 - ([(cyclopropylcarbonyl) (4-methoxybutyl) amine] piperidin-1-yl] -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide (example of compound 113); N- [ (2S) -4- { 4 - ([(cyclohexylcarbonyl) (4-methoxybutyl) amine] piperidin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methyl-benzamide ( example of compound 114); N - [(2S) -4-. {4- ([benzoyl (4-methoxybutyl) amino] pyridin-1-yl] -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide (example of compound 115); N - [(2S) -4-. {4- [cyclohexyl (propionyl) l-amyl] piperidin-1-yl} -2- ( 3,4-dichlorophenyl) butyl] -N-methylbenzamide (example of compound 116); N - [(2S) -4-. {4- [cyclohexyl (cyclopropylcarbonyl) -amino] piperidin-1-; 1.} - 2- (3,4-dichlorophenyl) butyl] - N -methylbenzamide (example of compound 117); N - [(2S) -4-. {4- [cyclohexyl (c) clohexylcarbonyl) amino] piperidin-1-yl.} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide (example of compound 118); N - [(2S) -4-. { 4- or [benzoyl (cyclohexyl) amino] pyridin-1-yl] -2- (3,4-dichlorophenyl) butyl] -N- methylbenzamide (example of compound 119); N - [(2S) -2- (3,4-dichlorophenyl) -4-. { 4 - [(1-methyl-piperidin-4-yl) (propionyl) amino] piperidin-1-yl} butyl] -N-methylbenzamide (example of compound 120); N - [(2S) -4-. { 4 - [(cyclopropylcarbonyl) (1-methylpiperidin-4-yl) amino] -piperidin-1-yl} 2- (3,4-dichlorophenyl) -butyl] -N-methylbenzamide (example of compound 121); N - [(2S) - 5 4-. { 4 - [(cyclohexylcarbonyl) (1-methylpiperidin-4-yl) amino] -p -peridin-1-yl} -2- (3,4- dichlorophenyl) -butyl] -N-methylbenzamide (example of compound 122); and N-. { 1 - [(3S) -4- [Benzoyl (methylal) amino] -3- (3,4-dichlorophenyl) butyl] piperidin-4-yl} -N - [(1-methylpiperidin-4-yl) benzamide (example of compound 123). Example 37: Preparation of starting materials (compound III): Hld lile iva Illa lllb deprotection The commercially available compound 11 Id is reacted with tertiary butoxycarbonyl anhydride to deliver the lile compound which is then transformed into intermediate lllb under reductive amination conditions. The intermediate compound IIIb is acylated in the corresponding amide Illa. The amide Illa is then deprotected to provide intermediate compound III. Example 38: Preparation of? / - (cyclopropylmethyl) -? / - piperidin-4- ilpropanamide To a mixture of 1 g (5 mmol) of tere-butyl 4-oxopiperidine-1-carboxylate (lile compound), 0.39 ml (4.5 mmol) of 1-cyclopropylmethanamine and 0.56 g (6.8 mmmol) of 20% sodium acetate. of THF at room temperature under stirring were added 0.44 ml (7.75 mmol) of acetic acid. After stirring for 1 h, 1.93 g (9.1 mmol) of sodium triacetoxyborohydride was added to this mixture. After stirring for another 15 h, the mixture was concentrated in vacuo to dryness and redissolved in 50 ml of ether. The organic solution was extracted three times with 30 ml of 0.1 n aqueous HCl. The combined water layers were made alkaline by aqueous sodium hydroxide and then extracted three times with 30 ml of ether. The combined organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give 1.1 g of crude tert-butyl 4 - [(cyclopropylmethyl) amino] piperidine-1-carboxylate (lllb). To a solution cooled to 5 ° C of 1.1 g (4.3 mmol) of 4 - [(cyclopropylmethyl) -amino] piperidine-1-carboxylic acid tere-butyl ester (compound IIIb) and 1.13 ml (6.5 mmol) of N-ethyl -diisopropylamine in 25 ml of dichloromethane, 0.45 ml (5.2 mmol) of propanoglyl chloride in 3 ml of dichloromethane was added. After stirring for 2 h, the mixture was evaporated and redissolved in 50 ml of ether. The organic phase was washed sequentially 2 times with 30 ml of water, 2 times with 20 ml of 0.1 N aqueous sodium hydroxide, with 30 ml of 0.1 N aqueous hydrochloric acid, dried over sodium sulfate and concentrated to give 1.1 g of crude 4 - [(cyclopropylmethyl) (propionyl) amino] cyclohexane-carboxylic acid tert-butyl ester (compound IIIa). The solution of 1.1 g of 4 - [(cyclopropylmethyl) (propionyl) amine] -piperidine-1-tert-butylcarboxylate (compound IIIa) in 20 ml of 4 M hydrogen chloride in dioxane and 5 ml. of ethanol was stirred at room temperature for 15 h, then it was evaporated and redissolved in 50 ml of dichloromethane and sequentially washed 3 times with 20 ml of aqueous potassium carbonate (10%), with 30 ml of water , dried over sodium sulfate and concentrated in vacuo to give 0.45 g of? / - (cyclopropylmethyl) -? / - piperidin-4-ylpropanamide (compound III) as a colorless oil. The preparation of the required series of 4-substituted piperidines (see above) was performed according to the described procedure. The compounds of formula I listed in Table 14 below are prepared according to the procedure described in the preceding examples or according to analogous procedures thereto.

Table 16 contains analytical data from mass spectroscopy, indicating the retention time in relation to the observed molecular weight. Table 16: MS data and retention time 20 20 Example 39: 1 '- [4- (Benzoyl-methyl-amine) -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperdinyl-4'-carboxylic acid dimethylamide mg Corn starch 60 mg Lactose 300 mg Ethyl acetate is. The active substance, corn starch and lactose were made in a homogenous slurry using ethyl acetate. The paste was ground and the resulting granules were placed in a suitable tray and dried at 45 ° C to remove the solvent. The dried granules were passed through a mill and mixed in a mixer with the following adjuvants: Talc 5 mg Magnesium stearate 5 mg Corn starch 9 mg and then poured into capsules of 400 mg (= capsule size 0). Example 40: Capsules Containing 1 '- [4- (Benzoyl-Methyl-amino-J-S-1S-D-chloro-phenyl-butyl-1H-2-piperidinyl-4'-carboxylic acid methylamide Capsules were produced with the following composition per capsule: 4- (benzoyl-methylene-3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipperidinyl-4'-carboxylic acid methylamide Co 20 mg Corn starch 60 mg Lactose 300 mg Ethyl acetate is The active substance, corn starch and lactose were made in a homogeneous slurry using ethyl acetate, the paste was milled and the resulting granules were placed In a suitable tray and dried at 45 ° C to remove the solvent, the dried granules were passed through a mill and mixed in a mixer with the following adjuvants: Talc 5 mg Magnesium stearate 5 mg Corn starch 9 mg and then poured into 400 mg capsules (= capsule size 0). Example 41: Capsules containing 1 '- [4- (cyclohexanecarbonyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1, 4'] dimethylamide Bipiperidinyl-4'-carboxylic Capsules with the following composition per capsule were produced: 1 '- [4- (cyclohexanecarbonyl-methyl-amine) -3- (3,4-dichloro-phenyl) -butyl] dimethylamide [1, 4 '] bipiperidinyl-4'-carboxylic acid 20 mg Corn starch 60 mg Lactose 300 mg Ethyl acetate is. The active substance, corn starch and lactose were made in a homogenous slurry using ethyl acetate. The paste was ground and the resulting granules were placed in a suitable tray and dried at 45 ° C to remove the solvent. The dried granules were passed through a mill and mixed in a mixer with the following adjuvants: Talc 5 mg Magnesium stearate 5 mg Corn starch 9 mg and then poured into 400 mg capsules (= capsule size 0 ). Example 42: Capsules containing 1 '- dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(4-fluoro-benzoyl) -methyl-amino] -butl} - [1, 4 '] bipperidinyl-4'-carboxylic acid Capsules with the following composition per capsule were produced: dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(4-fluoro-benzoyl) -methyl-amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid 20 mg Corn starch 60 mg Lactose 300 mg Ethyl acetate is.

The active substance, corn starch and lactose were made in a homogenous slurry using ethyl acetate. The paste was ground and the resulting granules were placed in a suitable tray and dried at 45 ° C to remove the solvent. The dried granules were passed through a mill and mixed in a mixer with the following adjuvants: Talc 5 mg Magnesium stearate 5 mg Corn starch 9 mg and then poured into 400 mg capsules (= capsule size 0 ).

Claims (22)

1. CLAIMS 1.- Compounds of general formula I wherein: R1 is selected from the group consisting of: alkyl and cycloalkyl, R2 is selected from the group consisting of: alkyl, cycloalkyl,
2. Aryl, alkylenearyl, alkenylenaryl, heteroaryl and heterocyclic ring, R3 and R4 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl, cyano and carboxyalkyl, X is selected from the group consisting of: CR6 and nitrogen, R5 is selected of the group consisting of alkyl optionally substituted with (CO) mNR9R10, cycloalkyl optionally substituted with - r (CO) mNR9R10, and NR7R8, R6 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and (CO) mNR9R10, R7 and R8 are independently selected from the group consisting of: alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, COalkyl, COAaryl, or wherein R7 and R8 together form a 5- to 7-membered ring, optionally containing an additional heteroatom or 0 selected from the group consisting of nitrogen and oxygen, wherein said ring may be substituted with CONR9R10, and wherein in a 6-membered ring none of the ring atoms is replaced by carbonyl, R9 and R10 are independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, or wherein R9 and R10 together form a ring of 5 to 7 members, which optionally contains a additional heteroatom, m is selected from 0 or 1, and salts by acid addition, physiologically compatible, of formula I. 2. Compounds according to claim 1, wherein R1 is methyl.
3. 3. Compounds according to any of claims 1 or 2, wherein R3 and R4 are independently selected from the group consisting of: hydrogen, fluorine, chlorine, preferably hydrogen or chlorine.
4. 4. Compounds according to any of the preceding claims, wherein X is CR6, wherein R5 is NR7R8, and wherein R6 is (CO) mNR9R10 with m = 1.
5. 5. Compounds according to any of the preceding claims, wherein X is N, wherein R5 is cycloalkyl substituted with (CO) mNR9R10 and m = 1.
6. 6. Compounds according to any of the preceding claims, wherein R7 and R8 together form a 6-membered ring or wherein R7 and R8 together form a 6-membered ring substituted with CONR9R10.
7. 7. - Compounds according to any of the preceding claims, wherein R9 and R10 are both methyl, or wherein R9 and R10 together form a 6-membered ring, or wherein R9 and R10 together form a 5-membered ring substituted with carbonyl .
8. 8. Compounds according to any of the preceding claims, wherein R2 is selected from the group consisting of: Ci to C2o alkyl; C3 to C20 cycloalkyl; C2 to C2o alkenyl, wherein each of R11 to R16 are independently selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, hydroxyl, alkoxy, cyano, N (H) C (O) O-alkyl, aminoalkyl, dialkylamino, OCF3, CF3 , carboxyalkyl, S (0) 2 NH2, phenyl, alkyl and cycloalkyl, wherein each of R18 and R19 are independently selected from the group consisting of: hydrogen, cyano and aryl, where t is 0 or 1, wherein each Q is independently selected from the group consisting of: CR11 and N, wherein Y is selected from the group consisting of: CH, N and NO, wherein Z is selected from the group consisting of: C-benzyl, NH, N -benzyl, N-alkyl, O and S, wherein each is independently selected from the group consisting of: N and CR17; and wherein R17 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl, aryl, and thioalkyl.
9. 9. Compounds according to any of the preceding claims, wherein R5 is selected from the group consisting of:
10. 10. Compounds according to any of the preceding claims, selected from the group consisting of: Dimethylamide of 1'- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) acid -butl] - [1, 4 '] bipiperidinyl-4'-carboxylic acid; methylamide of l '- ^ - b-benzoyl-methyl-amino-J-S-2 S-dichloro-phenyl-J-butyl-3-yl] -iphenylperidyl-4'-carboxylic acid, dimethylamide of 1' - [4] - (cyclohexanecarbonyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipyperidine-carboxylic acid, dimethylamide of 1' -. { 3- (3,4-dichloro-phenyl) -4 - [(4-fluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipperidyl-4'-carboxylic ester 4-. { [2- (3,4-Dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4'-piperiperidinyl-l '-i-butyl-methyl-carbamoyl] -phenyl acetic acid, dimethylamide of acid 1, -. {3- (3,4-Dichloro-phenyl) -4 - [(4-hydroxy-benzoyl) -methyl-amino] -butyl} - - [1,4 '] -piperidinyl-4'- carboxyl, ester 2- { [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4 '] bipiperdin'l-1' -il) -butyl ] -methyl-carbamoyl.} -phenyl of acetic acid, 1-4 - [(3-chloro-4-fluoro-benzoyl) -methyl-amino] -3- (S ^ -) dimethylamide dichloro-phenyl-butyl-1-bipiperidine-1'-carboxylic acid dimethylamide 1'-. {3- (3,4-dichloro-phenyl) -4 - [(3,5-difluoro-benzoyl) -methyl) -amino] -butyl.} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide 1' - [4 - [(5-chloro-2-fluoro-benzoyl) -methyl-amino] -3 - (3,4-dichloro-phenyl) -butyl] - [1,4 '] -piperidinyl-4'-carboxylic acid dimethylamide 1'-. {3- (3,4-dichloro-phenyl) - 4- [methyl- (naphthalene-1-carbonyl-3-cyano) -amino] -butyl} - - [1,4'] bipiperidinyl-4'-carboxylic acid dimethyl ester 1'-. {3- (3,4-Dichloro-phenyl) -4- [(2-hydroxy-benzoyl) -methyl] -butyl acid ilamide} - [1, 4 '] bipiperidinyl-4, -carboxylic, dimethylamide of the acid 1 '-. { 3- (3,4-dichloro-phenyl) -4 - [(2,4-difluoro-benzoyl) -methyl-amino] -butyl} - [l ^ 'bipiperidiniW-carboxylic acid, dimethylamide 1' -. { 3- (3,4-dichloro-phenyl) -4 - [(3,4-difluoro-benzoyl) -methyl-amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4 - [(2,5-difluoro-benzoyl) -methyl-amino-butyl-H-bipiperidine-M-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4- [meth] - (2,3,4-trifluoro-benzoyl) -methyl-amino] -butyl} - [1, 4,] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (1-oxy-pyridine-4-carbonyl) -amino] -butyl} - [1 ^ bipiperidiniW-carboxylic acid, dimethylamide 1 '- [4 - [(6-chloro-pyridine-3-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [I] bipiperidine W-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-3-carbonyl) -amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide 1' - [4 - [(3-benzyl-2-methylsulfanyl-3H-imidazole-4-carbonyl) -methyl-amino] -3 - (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipyperidinyl-4'-carboxylic acid dimethylamide 1' -. { 3- (3,4-dichloro-phenyl) -4- [methyl- (4-oxo-2-phenyl-4H-chromene-3-carbonyl) -amino] -butyl} - [1 ^ 'jipipiperidin and W-carboxylic acid, dimethylamide of 1' - [4- (cyclopropanecarbonyl-methylamino) -3- (3,4-dichloro-phenyl) -butyl] - [1, 4 '] β-piperidinyl-4'-carboxylic acid, dimethylamide 1' - [4- (cyclopentanecarbonyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4 b1pperidinyl-4'-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-methylamino-benzoyl) -amino] -butyl} - [1, 4 '] bipiperdinedyl-4'-carboxylic acid, N- [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [I] bipyperidinyl-1-i- butyl-N-methyl-phthalamic acid, 1'-. {3- (3,4-dichloro-phenyl) -4 - [(4-methoxy-benzoyl) -methyl] -butyl} dimethylamide. - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1' - [4 - [(biphenyl-4-carbonyl) -met-1-amino] -3- (3,4-dichloro-phenyl) ) -butyl] - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide 1'-. {3- (S ^ -dichloro-phenylH-KS.S-diphenyl-propioni-methyl-aminol-butyl) -fl ^^ bipiperidiníW- carboxylic acid, dimethylamide 1 '- (3- (3,4-dichloro-phenyl) -4- { [3- (4-hydroxy-phenyl) -propionyl] -methyl-amino}. ) - [1 ^ 'IbipiperidiniW-carboxylic acid, dimethylamide 1' -. { 3- (3,4-dichloro-phenyl) -4- [methyl- (1-methyl-1 H -pyrrolo-2-carbonyl) -amino] -butyl ester} - [1, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4- [(furan-2-carbonyl) -methyl-amino] -butyl} - [1 ^ 'jbipiperidiniW-carboxylic acid, dimethylamide 1' -. { 3- (3,4-dichloro-phenyl) -4- [methyl- (naphthalene-2-carbonyl) -amino] -butyl} - [l ^ bipyperidine W-carboxylic acid, dimethylamide 1 '- [4 - [(2-biphenyl-4-yl-acetyl) -methyl-aminol-S-1S ^ -dichloro-phene-butyl-1-phenyl-piperidinyl ^ '-carboxylic acid, dimethylamide 1' - [4-. { [3- (4-chloro-phenyl) -acyloyl] -methyl-amino} -3- (3,4-dichloro-phenyl) -butyl] - [1'-JbipiperidiniW-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (1 H -pyrrolo-2-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidine W-carboxylic acid, dimethylamide of 3- (3,4-dichloro-phenyl) -4 - [(furan-2-carbonyl) -methyl-amino] -butyl} - [1, 4 '] biphenylperidyl-4'-carboxylic acid, 1'- dimethylamide. { 3- (3,4-dichloro-phenyl) -4- [methyl- (thiophene-2-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-Dichloro-phenyl) -4- [methyl- (thiophene-3-carbonyl) -amino] -butyl-1-pyridine-carboxylic acid, dimethylamide of 1 '-. { 3- (3,4-dichloro-phenyl) -4 - [(1 H -indole-3-carbonyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1' -. { 3- (3,4-dichloro-phenyl) -4 - [(2-1H-indol-3-yl-acetyl) -methyl-amino] -butl} - [1, 4 '] bipperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(1 H -indole-5-carbonyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide 1' -. { 3- (3,4-dichloro-phenyl) -4- [meth] - (pyrazine-2-carbonylamino-butyl-II-1-pyridine-1-carboxylic acid dimethylamide). (3,4-dichloro-phenyl) -4- [methyl- (pyridine-2-carbonyl) -amino] -butyl} - - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide C. (3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-4-carbonyl) -amino] -butyl} - [1] -bipiperidinyl-carboxylic acid dimethylamide. 1'- acid. (3,4-dichloro-pheny!) -4- [methyl- (4-oxo-4H-chromene-2-carbonyl) -amino] -butyl} - [1, 4 '] bipyperidinyl-4'-carboxylic acid dimethylamide 1' -. { 3- (3,4-dichloro-phenyl) -4- [methyl- (4-sulfamoyl-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipperidinyl-4'-carboxylic acid, dimethylamide of 1' - [4 - [(4-chloro-3-sulfamoyl-benzoyl) -methyl-amino] -3- (3,4- dichloro-phenyl) -butyl H1, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1' -. { 3- (3,4-dichloro-phenyl) -4 - [(2-1 H-imidazol-4-yl-acetyl) -methyl-amino] -butyl} - [1, 4 '] bipiperitaminyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyrridin-2-yl-acetyl) -amino] -butyl} - [1, 4,] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-3-yl-acetyl) -amino] -butyl} - [1, 4 '] bipyperidinyl-4'-carboxylic acid, dimethylamide of 1, -. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-4-yl-acetyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide 1' - [4 - [(1-acetyl-pperidine-4-carbonyl) -methyl-amino] -3- (3, 4-dichloro-phenyl] -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4- [methyl- (tetrahydro-pyrn-4-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, 4- ({[2- (3,4-dichloro-phenol) -4- (4'-) tert-butyl ester. dimethylcarbamoyl- [1, 4 '] bipiperidinyl-1'-yl) -butyl] -methyl-carbamoyl.} - phenyl) -carbamic acid dimethylamide of l' -IS-2S-dichloro-phenyl ^ - ^ S-ttrifluoromethyl-methoxyl-benzoyl-methyl-amino] -butyl H "-bipiperidine-carboxylic acid, dimethylamide 1 '- (3- (3,4-dichloro-phenyl) -4- { [2- (2, 4-di. {Trifluoromethyl}. Phenyl) -acetyl] -methyl-amino} -butyl) - [1,4,] biphenylperidyl-4'-carboxylic acid dimethylamide. '-. { 3- (3,4-dichloro-phenyl) -4-. { [2- (2,6-dihydroxy-pyrimidn-4-yl) -acetyl] -methyl-amino} -butyl) - [1, 4 '] bipiperidinyl-4'-carboxylic acid, tere-butyl ester of 4- acid. { [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4 '] bipiperidinyl-1'-yl) -butyl] -methylcarbamoyl} -piperidine-1-carboxylic acid, dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4 - [(1 H-imidazole-4-carbonyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, (1- {. [2- (3,4-dichloro-phenyl) -4- (4'-) - butyl ester. dimethylcarbamoyl- [1,4 '] bipperidinyl-1'-yl) -butyl] -methylcarbamoyl} -2-phenyl-ethyl) -carbamic acid, [2- (3,4-dichloro-phenyl) -4- (4'- dimethylcarbamoyl- [1,4'-bipiperidinyl-l-yl] -butyl tert-butyl ester. -butyl] -methylcarbamic acid dimethylamide 1 '-. { 3- (3,4-dichloro-phenyl) -4 - [(furazan-3-carbonyl) -methyl-amino] -butyl} - [1, 4 '] b.p.peridinyl-4'-carboxylic acid dimethylamide of 1-IS-2S-dichloro-phenylH- [(2,2-difluoro-benzo [1, 3] ] dioxol-5-carbonyl) -meti-amino] -butyl} - [1, 4 '] bipyperidinyl-4'-carboxylic acid dimethylamide 1' -. { 3- (3,4-dichloro-phenyl) -4- [methyl- (1 H -pyrrolo-3-carbonylamino-butyl-1H-1-piperidinyl) -carboxylic acid dimethylamide 1 '- (3- (3) 4-dichloro-phenyl) -4- { [3- (4-fluoro-phenyl) -5-methyl-isoxazole-4-carbonyl] -methyl-amino} -butyl) - [1,4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide 1 '- (3- (3,4-dichloro-phenyl) -4-. {[[5- (4-methoxy-phenyl) -oxazole-4-carbonyl] ] -methyl-amino} -butyl) - [1,4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of l' ^ S-^ S ^ -dichloro-phenylH ^ methyKd-methyl-l- phenyl-1 H- [1,2,3] triazole-4-carbonyl) -amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid, dimethylamide of 1' - [4 - [(benzofuran-5-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) - butyl-1-pyrimidine-carboxylic acid dimethylamide 1'-. {3- (3,4-dichlorophenyl) -4- [methyl- (5-methyl-benzo [b] thiophene-2-carbonyl) ) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of l' - ^ - ^. S-bis-trifluoromethyl-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipperidinyl-4'-carboxylic acid; dimethyllamide of 1 '- [4 - [(2-bromo-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl-1-Jbipiperidine-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(2-fluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipperidinyl-4'-carboxylic acid, dimethylamide 1' - [3- (3,4-dichloro-phenyl) -4- (methyl-pentafluorobenzoyl-amine) -butyl Jbipiperidine W-carboxylic acid, dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4 - [(2,6-difluoro-benzoyl) -methyl-amino] -butyl} - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1, - [4 - [(2,4-dichloro-benzoyl) -methyl-amino] -3- (3,4-dichloro- phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1' - [4 - [(2,6-dichloro-benzoyl) -methyl-amino] -3- (3,4 -dichloro-phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1, -. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-trifluoromethyl-benzoyl-J-aminol-butyl-1H-1-piperidinyl-carboxylic acid, dimethylamide of 1'-. {3- (3,4-dichloro) phenyl) -4- [methyl- (2-methyl-benzoyl) -amino] -butyl} - - [1,4'] bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. {3- ( 3,4-dichloro-phenyl) -4 - [(3-fluoro-benzoyl) -methyl-amino] -butyl} - [1,4 '] -piperidinyl-4'-carboxylic acid dimethylamide - [4 - [(3-chloro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl] -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1 '- [4 - [(3,4-dichloro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl-butyl-1-bipiperidine-carboxylic acid, dimethylamide of 1'-. {3 - (3,4-dichloro-phenyl) -4 - [(3-methoxy-benzoyl) -methyl-amino] -butyl} - - [1,4] bipiperidinyl-4'-carboxylic acid , dimethylamide of 143- (3,4-dichloro-phenyl) -4- [methyl- (3-trifluoromethyl-benzoyl) -amino] -butyl} - [1, 4 '] b Piperidinyl-4'-carboxylic acid, dimethylamide 1 '- [4 - [(4-chloro-benzoyl) -methyl-amino] - 3- (3,4-Dichloro-phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(4-methoxy-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (4-trifluoromethyl-benzoyl) -amino] -butyl} - [1, 4,] bipyperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(4-methyl-benzoyl) -methyl-amino-butyl-1H-1-piperidine-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-pheny!) -4 - [(2,2-dimethyl-propionyl) -methyl-amino] -butl} - [1, 4,] bipiperidinyl-4, -carboxylic acid, dimethylamide 1 '- [3- (3,4-dichloro-phenyl) -4- (methyl-phenylacetylamino) -butyl] - [1, 4] '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-phenyl-cyclopropanecarbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide 1' - [4 - [(4-cyano-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butl] - [1, 4,] bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4- [meth] - (naphthalene-1-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1' -4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino] -3- (3,4 -dichloro-phenyl) -butyl] - [1 ^ 'IbipiperidiniM'-carboxylic acid, dimethylamide 1' - [4- (benzoyl-methyl-amino) -3-phenyl-butyl] - [1,4 '] bipiperidine l-4'-carboxylic acid methyl ethyl amide 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl- [1 ^' jbipiperidiniW- carboxylic, N-. { 2- (3,4-dichloro-phenyl) -4- [4- (1-dimethylcarbamoyl-cyclohexyl) -piperazin-1-yl] -butyl ester} -N-methyl-benzamide, 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1,4] dimethylamide, bipiperidinyl -2-carboxylic; 1 '- [4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] dimethyl amide pyrrolidin-1-yl-piperidine-4-carboxylic acid, dimethylamide of 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] -4-pyrrolidin-1- il-piperidine-4-carboxylic acid, N- [4- [4- (cyclopropylmethyl-propionyl-amino) -piperidin-1-yl] -2- (3,4-dichloro-phenyl) -butyl] - N-methyl-benzamide, N-. { 2- (3,4-dichloro-phenyl) -4- [4- (isopropyl-propionyl-amine) -piperidin-1-yl] -butyl} -N-methyl-benzamide, N-. { 2- (3,4-dichloro-phenyl) -4- [4- (phenyl-propionyl-amino) -piperidin-1-yl] -butyl} -N-methyl-benzamide, N- [4- [4- (butyl-propionyl-amino) -piperidin-1-yl] -2- (3,4-dichloro-phenyl) -butyl] -N-methyl -benzamide, N- [4- [4- (butyl-cyclopropanecarbonyl-amino) -piperidin-1-yl] -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide , N- [4- [4- (Butyl-cyclohexanecarbonyl-amino) -piperidin-1-yl] -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzam N- [4- [4- (benzoyl-butyl-amine) -piperidin-1-yl] -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide, N- ( 2- (3,4-dichloro-phenyl) -4-. {4 - [(4-methoxy-butyl) -propionyl-amino] -p -peridin-1-yl}. -butyl) -N-methyl -benzamide, N- [4-. { 4- [Cyclopropanecarbonyl- (4-methoxy-butyl) -amino] -piperidin-1-yl} -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide, N- [4-. { 4- [cyclohexanecarbonyl- (4-methoxy-butyl) -amino] -piperidin-1-yl} -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide, N- [4-. { 4- [benzoyl- (4-methoxy-butyl) -amino] -piperidin-1-yl} -2- (3,4-dichloro-phenyl) -butyl] -N-methyl-benzamide;
11. N- [4-. { 4- [cyclohexyl (propionyl) amino] piperidin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide, N- [4-. { 4- [Cyclohexyl (cyclopropylcarbonyl) -amino] piperidin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide, N- [4-. { 4- [Cyclohexyl (cyclohexylcarbonyl) -amino] piperidin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide, N- [4-. { 4- [benzoyl (cyclohexyl) amino] piperdin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide; N- [2- (3,4-dichlorophenyl) -4-. { 4 - [(1-methylpiperidin-4-yl) - (propionyl) amino] piperidin-1-yl} butyl] -N-methylbenzamide, N- [4-. { 4 - [(cyclopropylcarbonyl) (1-methylpiperidin-4-yl) amino] piperidin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide, N- [4-. { 4- [(cyclohexylcarbonyl) (1-methylpiperidin-4-yl) amino] piperidin-1-yl} -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide, N-. { 1- [4- [Benzoyl (methyl) amino] -3- (3,4-dichlorophenyl) butyl] piperidin-4-yl} -N- (1-methylpiperidin-4-yl) benzamide, N-. { 2- (3,4-dichloro-phenyl) -4- [4 '- (pyrrolidine-1-carbonyl) - [1,4'] bipiperidinyl-1'-I] -butyl} -N-methyl-benzamide, 1 '- [4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] -4-dimethylamide - (2-oxo-pyrroline-1-yl) -piperidine-4-carboxylic acid; . { 2- (3,4-dichloro-phenyl) -4- [4 '- (piperidine-1-carbonyl) - [1,4'] bipiperidinyl-1 '-yl] -butyl} 3-cyano-naphthalene-1-carboxylic acid methyl-amide, 1- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamido 1- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] -4-morpholine-4-yl-piperidine [1- (4- (Benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid isopropyl-methyl-amide 4-carboxylic acid, N-. { 2- (3,4-dichloro-phenyl) -4- [4- (piperidine-1-carbonyl) -4-pyrroline-1-yl-piperidin-1-yl] -butyl} -N-methyl-benzamide, 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] -4-pyrrolidin-1-yl-piperidine-4-diethylamide -carboxylic, N-. { 2- (3,4-dichloro-phenyl) -4- [4- (morpholine-4-carbonyl) -4-pyrrolidin-1-yl-piperidin-1-yl] -butyl} -N-methyl-benzamide, and salts by the addition of physiologically compatible acids, these compounds. 11. Compounds according to claim 10, selected from the group consisting of: 1 '- [4- (Benzoymethyl-amino) -3- (3,4-dichloro-phenyl) -butyl] dimethylamide [1, 4 '] bipiperidinyl-4'-carboxylic acid, methylamide of 1' - [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl] - [1, 4,] bipiperidinyl-4, -carboxylic acid, dimethylamide of 1 '- [4- (cyclohexanecarbonyl-methyl-amine) -3- (3,4-dichloro-phenyl-butyl-1H-1-piperidinyl) -carboxylic acid, dimethylamide of acid 1 '-. {3- (3,4-dichloro-pheny!) -4 - [(4-fluoro-benzoyl) -methyl-amino] -butyl] - [1,4'] bipiperid nyl-4'-carboxylic acid ester 4- { [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4 '] bipiperidinyl-1'-yl) - butyl] -methyl carbamoyl-acetic acid, dimethylamide of 1'-. {3- (3,4-dichloro-phenol) -4 - [(4-hydroxy) benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipperidyl-4, -carboxylic ester, 2- { [2- (3,4-dichloro-phenyl) ester) -4- (4, -dimethylcarbamoyl- [1,4 '] bipiperidinyl-1'-yl) -bu useful] -methyl-carbamoyl.} - phenyl of acetic acid, dimethylamide of 1 '- [4 - [(3-chloro-4-fluoro-benzoyl) -methyl-amino] -3- (3,4 -dichlorophenyl) -butyl] - [1,4] bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4 - [(3,5-difluoro-benzoyl) -methyl-amino] -butyl} - [1 ^ 'JbipiperidiniW-carboxylic acid, dimethylamide of 1' - [4 - [(5-chloro-2-fluoro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [I] bipiperidine W-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4- [methyl-naphthalene-1-carbonyl-S-cyano] -amino-butyl-1-phenyl-1-piperidinyl-carboxylic acid; dimethylamide of 1 '- acid. { 3- (3,4-dichloro-phenyl) -4 - [(2-hydroxy-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(2,4-difluoro-benzoyl) -methyl-amino] -butyl} - [1, 4,] bipperidinyl-4'-carboxylic acid; 1'- acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(3,4-difluoro-benzoyl) -methyl-amino-butyl-1H-1-piperidinyl-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(2,5-difluoro-benzoyl) -methyl-amino] -butyl} - [1 ^^ bipiperidinil ^ '- carboxylic acid, dimethylamide 1, -. { 3- (3,4-dichloro-phenyl) -4- [methyl- (2,3,4-trifluorobenzoyl) -methyl-amino] -butyl} - [1 ^ 'JbipiperidiniW-carboxylic acid, dimethylamide 1' - [4 - [(6-chloro-pyridine-3-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-3-carbonyl) -amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamide l' - ^ - Icyclopentanecarbonylmethyl-amino-S-1S-di-chloro-phenyl-butyl-1-pyridine-1-carboxylic acid dimethylamide 1'- . { 3- (3,4-dichloro-phenyl) -4- [methyl- (2-methylamino-benzoyl) -amino] -butyl} - [1, 4,] b-piperidinyl-4, -carboxylic acid, N- [2- (3,4-dichloro-phenol) -4- (4'-dimethylcarbamoyl) -1,4 '] bipiperitaminyl-l-butyl-N-methyl-phthalamic acid, dimethylamide of 1'-. {3- (3,4-dichloro-phenyl) -4 - [(4-methoxy) benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1' - (3- (3,4-dichloro-phenyl) -4 - { [3- (4-hydroxy-phenyl) -propionyl] -methyl-amino}. Butyl) - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1' - {3- (3,4-dichloro-phenyl) -4- [methyl- (1-methyl-1 H -pyrrolo-2-carbonyl) -amino] -butyl} - - [1,4 '] bipiperidinyl 4'-carboxylic acid, 1 '-. {3- (3,4-dichloro-phenyl) -4 - [(furan-2-carbonyl) -methyl-aminol-butyl-1H-1-piperidimethyl-carboxylic acid dimethylamide, 1'-. {3- (S ^ -dichloro-phenyl-1-phenyl-1-phthalene} -carbonylamino-butyl-1-phenyl} -carboxylic acid dimethylamide, 1'- (3. , 4-dichloro-phenyl) -4- [methyl- (1 H -pyrrolo-2-carbonyl) -amino] -butyl.} - [1,4 '] -piperidinyl-4'-c arboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4 - [(furan-2-carbonyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (thiophene-2-carbonyl) -amino] -butyl-1,4-bipperyl-4'-carboxy! co, dimethylamide of 1'- acid. { 3- (S ^ -dichloro-phenyl) -methyl-ithiofen-S-carboni-amino-butyl-1-phenyl-phenyl-phenylcarbonyl, dimethylamide of 3- (3,4-dichloro-phenyl) -4- [(1 H-indole-5-carbonyl) -methyl-aminol-butyl-1-phenyl-carboxylic acid, 1-dimethylamide. (3,4-dichloro-phenyl) -4- [methyl- (pyridine-2-carbonyl) -amino] -butl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-4-carbonylaminol-butyl-1-methyl-4-piperidinyl) -carboxylic acid dimethylamide. , 4-dichloro-phenyl) -4- [methyl- (4-oxo-4H-chromene-2-carbonyl) -amino] -butyl} - - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide. 1'-. {3- (3,4-Dichloro-phenyl) -4- [methyl- (4-sulfamoyl-benzoyl) -methyl-amino] -butyl} - [1,4 '] bipiperidinyl- 4'-carboxylic acid 1'- [4 - [(4-chloro-3-sulfamoyl-benzoyl) -methyl-amino] -3- (3,4-dichloro-phene-butyl-1-pyrimidine-carboxylic acid) dimethylamide , 1 '-. {3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-2-yl-acetyl) -amino] -butyl} - [] - dimethylamide. 1, 4,] bipiperidinyl-4'-carboxylic acid, dimethylamide 1, -. {3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-3-yl-acety-arnine) -butyl-2-piperidine-M'-carboxylic acid, dimethylamide 1'-. {3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-4-yl-acetyl) ) -amino] -butyl.} - [1, 4 '] bipiperidinyl-4'-carboxylic acid dimethylamide 1'- { 3- (3,4-dichloro-phenyl) -4- [methyl- (tetrahydro-pyran-4-carbonyl) -amino] -butyl} - [1 ^ bipiperidine-carboxylic acid, 4- ({. [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl) -1- [4] -butyl ester. '] bipryldinyl-1, -yl) -butyl] -methyl-carbamoyl.] - phenyl] -carbamic acid, dimethylamide of 1' -. { 3- (3,4-dichloro-phenyl) -4 - [(3- [trifluoromethyl-methoxy] -benzoyl) -methyl-amino] -butyl} - [1, 4,] b.p.peridinyl-4, -carboxylic acid, dimethylamide 1 '- (3- (3,4-dichlorophenyl) -4- { [2- (2,4- trifluoromethyl] -phenyl) -acetyl] -methyl-amino} -butyl) - [1,4 '] -piperidinyl-4'-carboxylic acid dimethylamide -. { 3- (3,4-dichloro-phenyl) -4 - [(2,2-difluoro-benzo [1,3] dioxol-5-carbonymethyl-aminol-butyl-II-L-piperidine-carboxylic acid dimethylamide 1 '- { 3- (3,4-dichloro-phenyl) -4- [methyl- (5-methyl-1-phenyl-1 H- [1,2,3] triazole-4-carbonyl) -amino ] -butyl} - [1 ^^ bipiperidinyl ^ '-carboxylic acid, dimethylamide 1' - [4 - [(benzofuran-5-carbonyl-methyl-aminol-S-IS-dichloro-phenyl-butyl-tl ^ 'Lipepiperidinylcarboxylic acid, dimethylamide 1' - [4 - [(2-bromo-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -
12. Butyl, Jbipiperidine-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(2-fluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-dichloro-phenyl) -4 - [(2,6-difluoro-benzoyl) -methyl-aminol-butyl-1-bipiperidine-carboxylic acid, dimethylamide of 1 '- [4 - [(2,4 - dichloro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'- acid. { 3- (3,4-Dichloro-phenyl) -4- [methyl- (2-trifluoromethyl-benzoyamino] utilHybibiperidine-carboxylic acid, dimethylamide of 1 '-. {3- (3,4 -dichloro-phenyl) -4- [methyl- (2-methyl-benzoyl) -amino] -butyl} - [1,4'-bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. - (3,4-dichloro-phenyl) -4 - [(3-fluoro-benzoyl) -methyl-amino] -butyl} - [1> 4,] bipiperidinyl-4'-carboxylic acid, 1 '- [4 - [(3-chloro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipiperidinyl-4'-carboxylic acid dimethylamide , 1'-. {3- (3,4-Dichloro-phenyl) -4 - [(3-methoxy-benzoyl) -methyl-amino] -butyl} - [1, 4], dimethylamide ] bipiperidinyl-4'-carboxylic acid, dimethylamide 1 '-. {3- (3,4-dichloro-phenyl) -4- [methyl- (3-trifluoromethyl-benzoyl) -amino] -butyl}. - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide 1'-. {3- (3,4-dichloro-phenyl) -4 - [(4-methyl-benzoyl) -methyl] -amino] -butyl H1.4] b-piperidinyl-4'-carboxylic acid, dimethylamide 1 '- [4 - [(4-cyano-benzoyl) -me tyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1'-4 - [(3-cyano-naphthalene-1) -carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1 ^ 'jbipiperidiniW-carboxylic acid, dimethylamide of l' - ^ - b-benzoyl-methyl-amino-S-phenyl- butyl-1-pyrrolidinyl-carboxylic acid, ethyl-methyl-amide of 1 '- [4- (benzoyl-methyl-amino) -3- (3,4-dichloro-phenyl) -butyl- [1]' JbipiperidiniW-carboxylic, N-. { 2- (3,4-dichloro-phenyl) -4- [4- (1-dimethylcarbamoyl-cyclohexyl) -piperazin-1-yl] -butyl} -N-methyl-benzamide, acid dimethylamide. 1 '- [4- (benzoyl-methyl-amino ^ S-^ S ^ -dichloro-phenyl-butyl ^ -yl-1-piperidinyl ^ -carboxylic acid 1- [4 - [(3-cyano-naphthalene-1-dimethylamide]] -carbonyl) -methyl-amino] -3- (3,4- dichloro-phenyl) -butyl] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid, dimethylamide 1- [4- (benzoyl-methyl-amino) -3- (3 , 4-dichloro-phenyl) -butyl] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid, and physiologically compatible acid addition salts of these compounds. 12. Compounds according to claim 10, selected from the group consisting of: 1 '- [4- (benzoymethyl-amino) -3- (3,4-dichloro-phenyl) -butyl] dimethylamide [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1' - [4- (cyclohexanecarbonyl-methyl-amino) -3- (3,4-dichloro-phene-butyl-1-Jbipiperidinyl) carboxylic acid, dimethyl amide of 1'-. {3- (3,4-dichloro-phenyl) -4 - [(4-fluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, 4- {[2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1,4 '] bipiperidinyl-1'-yl) -butyl ester] -methyl-carbamoyl.} - phenyl of acetic acid, dimethylamide of 1 '-. {3- (3,4-dichloro-phenyl) -4 - [(4-hydroxy-benzoyl) -methyl-amino] -butyl .-- - [1,4] bipiperidinyl-4'-carboxylic acid ester 2- { [2- (3,4-dichloro-phenyl) -4- (4'-dimethylcarbamoyl- [1, 4] '] bipiperidinyl-1'-l) -butyl] -methyl-carbamoyl} -phenyl-acetic acid, 1' - [4 - [(3-chloro-4-fluoro-benzoyl) - dimethylamide methyl-am ino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid dimethylamide. { 3- (3,4-dichloro-phenyl) -4 - [(3,5-difluoro-benzoyl-J-methyl-aminol-butyl-1-ethyl} -bipiperidine-carboxylic acid, dimethylamide of 1 '- [4 - [(5- chloro-2-fluoro-benzoyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide of 1' - {3- (3,4-Dichloro-phenyl) -4- [methyl- (naphthalene-1-carbonyl-3-cyano) -amino] -butyl} - [1, 4 '] b piperidinyl-4'-carboxylic acid, dimethylamide 1 '-. {3- (3,4-dichloro-phenyl) -4 - [(2-hydroxy-benzoyl) -methyl] -butyl}. - [1, 4 '] bipperidinyl-4'-carboxylic acid dimethylamide 1'-. {3- (3,4-dichloro-phenyl) -4 - [(2,4-difluoro -benzoyl) -methyl-amino] -butyl} - [1,4'-bipiperidinyl-4-carboxylic acid dimethylamide 1'-. {3- (3,4-dichloro-phenyl) -4- [(3,4-difluoro-benzoyl) -methyl- aminoJ-butylHbipiperidiniM'-carboxylic acid dimethylamide 1'-. { 3- (3,4-dichloro-phenyl) -4 - [(2,5-difluoro-benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipyperidinyl-4'-carboxylic acid dimethylamide 1' - [4 - [(6-chloro-pyridine-3-carbonyl) -methyl-amino] - S-ÍS dichloro-phene-butyl H &sub1; LipoipiperidineM-carboxylic acid dimethylamide 1'- ^ - (cyclopentanecarbonyl-methyl-amino-S-1S-dichloro-phenyl-butyl-II-lbipiperidinyl-4'-carboxylic acid, dimethylamide 1'-. 3- (3,4-dichloro-phenyl) -4 - [(furan-2-carbonyl) -methyl-amino] -butyl} - [1,4'-bipperidinyl-4'-carboxyl] co, dimethyl amide of 1'-. {3- (3,4-dichloro-phenyl) -4- [methyl- (pyridine-2-carbonyl) -amino] -butyl}. [1,4] bipiperidinyl-4'-carboxylic acid dimethylamide 1'-. {3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-2-yl-acetyl- aminoj-butyl-1-bipiperidine-carboxylic acid, dimethyllamide 1'-. {3- (3,4-dichloro-phenyl) -4- [methyl- (2-pyridin-3-yl-acetyl) -amino] -butyl.} - [1,4] bipiperidinyl-4'-carboxylic acid dimethylamide 1 '-. {3- (3,4-dichloro-phenyl) -4 - [(3 - [trifluoromethyl-methoxy] -benzoyl) -methyl-amino] -butyl} - [1, 4 '] bipiperidinyl-4'-carboxylic acid, dimethylamide 1' -. { S-1S ^ -dichloro-phenylH-tmethyl-d-methyl-1-phenyl-1 H- [1,2,3] triazole-4-carbonyl-J-aminol-butyl-1-ylpiperidine-carboxylic acid, dimethylamide of acid 1 '- [4 - [(benzofuran-5-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] -piperidinyl-4'-carboxylic acid, dimethylamide of 1 '-4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] - [1,4'] bipperidinyl- 4'-carboxylic acid, dimethylamide 1 '- [4 - [(3-cyano-naphthalene-1-carbonyl) -methyl-amino] -3- (3,4-dichloro-phenyl) -butyl] -4-pyrrolidine -1-yl-piperidine-4-carboxylic acid, and physiologically compatible acid addition salts of these compounds. 13.- Pharmaceutical composition comprising: (a) a pharmacologically effective amount of a compound of formula I, 5 wherein: R1 is selected from the group consisting of: alkyl and cycloalkyl, R2 is selected from the group consisting of: alkyl, cycloalkyl, aryl, alkylenaryl, alkenylenyl, heteroaryl and heterocyclic ring, R3 and R4 are independently selected from the group consists of: hydrogen, halogen,
13. Hydroxyl, cyano and carboxyalkyl, X is selected from the group consisting of: CR6 and nitrogen, R5 is selected from the group consisting of alkyl optionally substituted with (CO) mNR9R10, cycloalkyl optionally substituted with (CO) mNR9R10, and NR7R8, R6 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and (CO) mNR9R10, R7 and R8 are independently selected - of the group consisting of: alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, COalkyl, COaryl, or wherein R7 and R8 together form a 5- to 7-membered ring, optionally containing an additional heteroatom selected from the group consisting of in nitrogen and oxygen, wherein said ring may be substituted with CONR9R10, and wherein in a ring of 6 0 members none of the ring atoms is replaced by carbonyl, R9 and R10 are independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, or wherein R9 and R10 together form a 5- to 7-membered ring, optionally containing an additional heteroatom, m is selected from 0 or 1, its salts by the addition of 5 acids, physiologically acceptable and b) adjuvants and / or excipients pharmaceutically acceptable, conventional
14. 14. Process for the preparation of compounds of general formula I wherein: R1 is selected from the group consisting of: alkyl and cycloalkyl, R2 is selected from the group consisting of: alkyl, cycloalkyl, aryl, alkyl, alkenylaryl, heteroaryl and heterocyclic ring, R3 and R4 are independently selected from the group it consists of: hydrogen, halogen, hydroxyl, cyano and carboxyalkyl, X is selected from the group consisting of: CR6 and nitrogen, R5 is selected from the group consisting of alkyl optionally substituted with (CO) mNR9R10, cycloalkyl optionally substituted with (CO) mNR9R10, and NR7R8, R6 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and (CO) mNR9R10, R7 and R8 are independently selected from the group consisting of: alkyl, cycloalkyl, aryl , alkylenearyl, alkyleneoxyalkyl, COalkyl, COaryl, or wherein R7 and R8 together form a 5- to 7-membered ring, optionally containing an additional heteroatom selected from the group consisting of nitrogen and oxygen, wherein said ring may be substituted with CONR9R10 , and wherein in a 6-membered ring none of the ring atoms is replaced by carbonyl, R9 and R10 are independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, or wherein R9 and R10 together form a ring of 5 to 7 members, optionally containing a additional heteroatom, m is selected from 0 or 1, and its physiologically acceptable acid addition salts, characterized in that: (a) compounds of formula I are prepared by reacting a compound of formula II with a compound of formula to result in a compound of general formula I which, optionally, is converted to its salt by physiologically compatible acid addition. O (b) compounds of formula I are prepared by reacting a compound of formula III with a compound of general formula IV to give a compound of the general formula V, the compound of general formula V is then hydrolyzed in an acidic medium to give a compound of general formula VI, the compound of general formula VI is then reacted with a compound of formula VII to result in a compound of general formula I which, optionally, is converted to its salt by physiologically compatible acid addition, (c) compounds of formula I are prepared by reacting a compound of formula X wherein Q is selected from the group consisting of: halogen, preferably bromine or iodine; and methylsulfonyl, with a compound of formula III to result in a compound of general formula I which, optionally, is converted to its salt by physiologically compatible acid addition.
15. 15. Use of compounds according to any of claims 1 to 12 for the production of pharmaceutical preparations for the treatment and / or prophylaxis of any pathology in which neurokinin A and / or NK.sub.2 receptors are involved or neurokinin B and / or NK.sub.3 receptors or both neurokinin A and neurokinin B and / or NK.sub.2 and NK.sub.3 receptors.
16. 16. Use of compounds according to any of claims 1 to 12, wherein R2 is a ring system of cyano-substituted naphthalene, for the production of pharmaceutical preparations for the treatment and / or prophylaxis of any pathology in which substance P and / or NK.sub receptors are involved. 1, or neurokinin A and / or NK.sub.2 receptors, or neurokinin B and / or NK.sub.3 receptors, or any combination of two or all three substance P, neurokinin A and neurokinin B and / or receptors of NK.sub.1, NK.sub.2 and NK.sub.3.
17. 17. Use according to any of claims 15 or 16 for the treatment and / or prophylaxis of pathologies of the respiratory, gastrointestinal, urinary, immune and cardiovascular systems and the central nervous system, as well as pain, migraine, inflammation, nausea and vomiting, and diseases of the skin.
18. 18. Use according to any of claims 15 to 17 for the treatment and / or prophylaxis of respiratory diseases, in particular asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, bronchitis, cough and rhinitis; skin diseases, in particular inflammatory reactions of the skin, allergic skin reactions and psoriasis; arthropathy diseases, in particular arthritis, vasculitis and systemic lupus erythematosus; functional or inflammatory disorders in the gastrointestinal tract, in particular pseudomembranous colitis, gastritis, acute and chronic pancreatitis, ulcerative colitis, Crohn's disease and diarrhea; bladder diseases such as cystitis and interstitial cystitis; cardiovascular diseases such as hypertension, cancer treatment, especially melanomas, gliomas, small cell and large cell lung cancers, diseases of the immune system, bipolar disorders; migraine; pain, anxiety, depression, cognitive disorders, somatic disorders related to stress, psychosis, in particular schizophrenia, mania, ski-affective disorder and panic disorders.
19. 19. Method to treat or prevent any pathology in which neurokinin A and / or NK.sub.2 receptors or neurokinin B and / or NK.sub.3 receptors are involved or both neurokinin A and neurokinin B and / or NK.sub.2 and NK.sub.3 receptors in mammals and humans, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, 5 wherein: R1 is selected from the group consisting of: alkyl and cycloalkyl, R2 is selected from the group consisting of: alkyl, cycloalkyl, aryl, alkylenaryl, alkenylenyl, heteroaryl and heterocyclic ring, R3 and R4 are independently selected from the group it consists of: hydrogen, halogen, hydroxyl, cyano and carboxyalkyl, X is selected from the group consisting of: CR6 and nitrogen, R5 is selected from the group consisting of alkyl optionally substituted with (CO) mNR9R10, cycloalkyl optionally substituted with (CO) ) mNR9R10, and NR7R8, R6 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and (CO) mNR9R10, R7 and R8 are independently selected - of the group consisting of: alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, COalkyl, COaryl, or wherein R7 and R8 together form a 5- to 7-membered ring, optionally containing an additional heteroatom selected from the group consisting of in nitrogen and oxygen, wherein said ring may be substituted with CONR9R10, and wherein in a ring of 6 0 members none of the ring atoms is replaced by carbonyl, R9 and R10 are independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, or wherein R9 and R10 together form a 5- to 7-membered ring, optionally containing an additional heteroatom; m is selected from 0 or 1, and salts by the addition of physiologically compatible acids of formula I.
20. 20. - Method to treat or prevent any pathology involving substance P and / or NK.sub.1 receptors, or neurokinin A and / or NK.sub.2 receptors or neurokinin B and / or NK.sub receptors .3 or both neurokinin A and neurokinin B and / or NK.sub.2 and NK.sub.3 receptors or any combination of two or all three substance P, neurokinin A and neurokinin B and / or NK.sub receptors. 1, NK.sub.2 and NK.sub.3 in mammals and humans, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, wherein: R1 is selected from the group consisting of: alkyl and cycloalkyl, R2 is selected from the group consisting of: alkyl, cycloalkyl, aryl, alkyl, alkenylaryl, heteroaryl and heterocyclic ring, R3 and R4 are independently selected from the group it consists of: hydrogen, halogen, hydroxyl, cyano and carboxyalkyl, X is selected from the group consisting of: CR6 and nitrogen, R5 is selected from the group consisting of alkyl optionally substituted with (CO) mNR9R10, cycloalkyl optionally substituted with (CO) mNR9R10, and NR7R8, R6 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and (CO) mNR9R10, R7 and R8 are independently selected from the group consisting of: alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, COalkyl, COAlkyl , or wherein R7 and R8 together form a 5- to 7-membered ring, optionally containing a heteroatom additional selected from the group consisting of nitrogen and oxygen, wherein said ring may be substituted with CONR9R10, and wherein in a 6-membered ring none of the ring atoms is replaced by carbonyl, R9 and R10 are independently selected from the group it consists of: hydrogen, alkyl, cycloalkyl, aryl, alkylenaryl, alkyleneoxyalkyl, or wherein R9 and R10 together form a 5- to 7-membered ring, optionally containing an additional heteroatom, m is selected from 0 or 1, and salts by addition of acids, physiologically compatible of formula I.
21. 21. Method for treating or preventing according to claim 18, wherein pathologies of the respiratory, gastrointestinal, urinary, immune and cardiovascular systems and of the central nervous system are involved, as well as pain. , migraine, inflammation, nausea and vomiting, and skin diseases.
22. 22. Method for treating or preventing according to claim 18 and / or wherein pathologies of respiratory diseases are involved, in particular asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, bronchitis, cough and rhinitis; skin diseases, in particular inflammatory reactions of the skin, allergic skin reactions and psoriasis; diseases of arthropathy, in particular arthritis, vasculitis and lupus erythematosus sistémico; functional or inflammatory disorders in the gastrointestinal tract, in particular pseudomembranous colitis, gastritis, acute and chronic pancreatitis, ulcerative colitis, Crohn's disease and diarrhea; bladder diseases such as cystitis and interstitial cystitis; cardiovascular diseases such as hypertension, cancer treatment, especially melanomas, gliomas, small cell and large cell lung cancers, diseases of the immune system, bipolar disorders; migraine; pain, anxiety, depression, disorders Cognitive disorders, somatic disorders related to stress, psychosis, in particular schizophrenia, mania, schizoaffective disorder and panic disorders.